Regan, Karen L. MSN, RN, APRN,BC, CCRN
The World Health Organization predicts that by the year 2020, depression and ischemic heart disease will be the 2 leading causes of premature death and years of life lost due to disability.1,2 These 2 conditions are alarming not only in their individual statistics but also in their high rate of concurrence. Although the exact correlation is unknown, rates of major depression are approximately 2 times higher in the postacute coronary syndrome (ACS) population (15%-23%) than in the general adult population (5%-9%), whereas rates of minor depression may be even higher.3 Researchers have repeatedly shown that depression in the post-ACS population is an independent risk factor for poor outcomes including higher rates of rehospitalization, patient noncompliance, and mortality while negatively affecting quality of life.3-5
Because of the adverse and life-threatening risks associated with depression, practitioners must monitor and provide prompt treatment if signs of depression are noted. Although various treatments for depression exist, practitioners must be mindful of choosing treatments for patients with post-ACS that pose no cardiac risks. Certain medications, namely tricyclic antidepressants such as imipramine, amitriptyline, nortriptyline, and desipramine, have been associated with undesirable cardiac effects such as tachycardia, orthostatic hypotension, intraventricular conduction delays, myocardial infarction, and even sudden cardiac death and are thus now contraindicated in patients with ACS.6-8 Healthcare professionals are faced with the challenge of developing and evaluating strategies to appropriately manage depression in the post-ACS population while maximizing benefits and minimizing risks. At the forefront of this investigation are newer antidepressive agents, selective serotonin reuptake inhibitors (SSRIs).7
Depression, Cardiac Disease, and SSRIs
Many theories on causes of both depression and the association between depression and ischemic heart disease exist. One major belief about depression is that it is linked to neurotransmitters and is precipitated by either deficient levels of these neurotransmitters (serotonin, norepinephrine, and/or dopamine) at the synaptic cleft or by a decreased response to these neurotransmitters at the postsynaptic neuron. Yet, these explanations may seem too simplistic for the multitude of depression's associated physiological manifestations.8,9 A few of these manifestations, which may be associated with its connection to coronary artery disease (CAD), include stiffening, remodeling, and narrowing of arteries (including the coronary arteries) and increased endothelial reactivity.8 Furthermore, depression has been shown to increase catecholamine release and increase plaque instability, thus increasing the risk for the development or progression of CAD in patients with depression.8 Such findings lend support to the theory that depression may precipitate CAD rather than the CAD precipitating depression.
Selective serotonin reuptake inhibitors work primarily by inhibiting the reuptake of the neurotransmitter, serotonin, by the presynaptic neurons, resulting in an increased amount of available serotonin at the synaptic cleft.9 Selective serotonin reuptake inhibitors also act in the bloodstream by decreasing the uptake of serotonin by platelets, which may pose some cardiovascular benefit.
Potential Benefits of SSRIs for the ACS Population
Serotonin is located both in the central nervous system and in the blood, principally in the platelets where it is stored and transported. Platelet activation and aggregation stimulate the release of the platelets' stored serotonin.10 It has been proposed that this released serotonin assists with clot stabilization and vasoconstriction, and although beneficial in most cases, these properties of serotonin may be detrimental during an acute coronary event.10 Selective serotonin reuptake inhibitors work by preventing the uptake of serotonin by the presynaptic neurons and by the platelets. Because SSRIs decrease the amount of serotonin stored by the platelets, less serotonin is released during platelet aggregation, and as such, SSRIs are proposed to have antithrombotic properties, which may be cardioprotective.10
Data for this article were obtained through a literature search in January through February 2007 of the electronic databases CINAHL, EMBASE, Ovid MEDLINE (R), and PubMed Plus using the keywords acute coronary syndrome, myocardial infarction, SSRIs, sertraline, paroxetine, fluoxetine, depression, depressive disorder, and major depression. Studies were then limited to those in the English language, with adult populations, with human subjects, within publication years 2002-2007, and which are primary research articles. Given the limited amount of pertinent studies retrieved, the search was further expanded to include 2000-2002. Abstracts were reviewed for their applicability to this subject, and reference lists of the applicable studies were also scanned for any additional studies. Six studies were found that specifically researched the use of SSRIs in the post-ACS population. Of note, one of these studies included any patient with cardiovascular disease and depression (however, 65% of those participants experienced ACS).11
The 6 studies noted in Table 1 will be discussed according to the outcomes researched and the study's contributions to this topic. These have been broken down to 3 main themes including safety, efficacy, and effect on mortality and morbidity of SSRIs in patients with post-ACS. The adverse effects noted with the use of SSRIs in each study will also be addressed.
The first double-blind placebo-controlled trial on the use of SSRIs in the postmyocardial infarction population was undertaken by Strik et al12 in 2000. This small study included 54 participants with major depression and within 3 to 12 months of myocardial infarction, who were randomized to receive either placebo or the SSRI fluoxetine. To determine the safety of the SSRI, these researchers compared electrocardiographic measurements, blood pressure measurements, and echocardiographic measurements, including left ventricular ejection fraction before and after SSRI treatment. Once variables including severity of myocardial infarction were considered, no differences between the 2 groups were observed. This prompted the researchers to conclude that although their study was limited by its small sample size, fluoxetine appeared to be safe for adults at least 3 months after myocardial infarction.12
Two years later, Glassman et al13 undertook the largest randomized control trial on the safety of SSRIs for depressed patients with post-ACS. This study, the Sertraline Antidepressant Heart Attack Randomized Trial, evaluated the safety and efficacy of sertraline use in patients within 30 days of hospitalization for unstable angina or an acute myocardial infarction and diagnosed with depression (major or minor). Participants in this study were randomized to receive either placebo or sertraline starting at 50 mg/d and increasing to the maximum dosage of 200 mg/d by week 12 of the study. Changes in the left ventricular ejection fraction, the electrocardiogram, blood pressure, heart rate, and basic laboratory data during the 16-week study were used to measure the medications' safety. There were no differences found in any measurements between the placebo group and the sertraline group, leading these researchers to propose that the SSRI, sertraline, appeared safe for use in depressed patients with recent myocardial infarction or unstable angina.13
These results were concordant with those of a third recent study by Lesperance et al,11 the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy Trial. Lesperance et al11 evaluated the use of the SSRI, citalopram, and interpersonal therapy (IPT) for the treatment of depression. These researchers found no differences in blood pressure or electrocardiograms of patients taking citalopram versus a placebo.
For the treatment of depression in patients with CAD, Lesperance et al11 sought to determine the efficacy of both citalopram and IPT, a commonly recommended short-term psychotherapy for depression that focuses on the patients' interpersonal relationships and conflicts. These researchers randomly assigned 284 severely depressed cardiac patients to IPT and clinical management or clinical management alone and then to citalopram or placebo. Routine clinical management was defined as 20- to 25-minute visits in which the participants were provided reassurance, encouragement, and information on depression and medication. After 12 weeks of therapy, all participants randomized to take citalopram had greater improvements in depression scores compared with the placebo group, with an average mean decrease in the Hamilton depression (HAM-D) rating scale of 3.3 points (effect size of 0.33) and in the Beck Depression Inventory II scores of 3.61 points (effect size of 0.33). See Table 2 for the definitions of HAM-D, BDI-I, and Beck Depression Inventory II. A preplanned subgroup analysis of patients taking citalopram showed the greatest improvement in the recurrently depressed population. However, first-time-depressed patients showed no statistically significant improvement in depression scores with the use of citalopram compared with that of placebo. Interestingly, demonstrable benefits were noted with the use of citalopram but not with IPT.
Lesperance et al11 noted similar findings from Glassman et al,13 with both groups of researchers finding that of those participants assigned to take an SSRI, recurrently depressed participants had greater improvements in depression scores than that of first-time-depressed participants. Glassman et al13 found that those participants with at least 2 episodes of major depression before this episode and severely depressed participants (HAM-D scores greater than or equal to 18) who were randomized to the SSRI therapy showed significantly greater improvements in depression scores compared to the same subpopulation in the placebo group. Similarly, there was no conclusive advantage of the SSRI over placebo in first-time-depressed participants.
The participants in the Glassman et al13 study were also included in a secondary study by Swenson et al,5 which evaluated the efficacy of the SSRI, sertraline, on subjective quality of life and satisfaction ratings (based on the use of a previously published assessment tool, the Quality-of-Life, Enjoyment, and Satisfaction scale) by comparing ratings before, throughout, and after SSRI therapy (24 weeks).5 Swenson et al5 found that depression was the strongest predictor of decreased quality of life ratings and it negatively impacts subjective quality of life appraisal.5 These researchers found comparable improvements in quality of life scores in both the SSRI group and the placebo group but found statistically significant greater improvements in a number of subjective quality of life appraisals in the recurrently depressed participants taking an SSRI over the recurrently depressed participants in the placebo group.5 However, this finding was limited because of the small size of this subgroup of participants.
Mortality and Morbidity Rates With the Use of an SSRI
Numerically fewer serious adverse cardiac events, defined as rehospitalization for cardiac event, occurred in participants taking SSRIs compared to the placebo group by both Strik et al12 and by Glassman et al.13 Yet, neither study demonstrated statistical significance. Subsequent studies support this trend toward decreased mortality in patients taking SSRIs compared to those taking placebos.14,15
Another study published by the Writing Committee for the ENRICHD Investigators,14 the Enhancing Recovery in Coronary Heart Disease14 Patients Randomized Trial, sought to determine if treating depression with cognitive behavioral therapy (CBT, a short-term psychotherapy, similar to IPT and also used for depression, that attempts to modify patients' beliefs and behaviors) supplemented by an SSRI soon after a myocardial infarction would decrease the morbidity and mortality greater than routine care alone. Routine care was defined as usual care provided to the participant from his or her physician, in which the participant could be prescribed an antidepressant according to the physician's discretion. This study randomized 2,481 depressed patients with postmyocardial infarction to receive either CBT supplemented by an SSRI if depression scores remained high or routine care. Although the researchers found no decrease in morbidity or mortality in patients treated with CBT, after reviewing the results, they noted that antidepressant use was associated with fewer incidences of both reinfarction and death (21.5%) compared with no antidepressant use (26%). Of note, participants were not randomized to antidepressant treatment but rather to CBT. These findings prompted researchers to examine the morbidity and mortality rates of those participants taking SSRIs versus those taking either another antidepressant or no antidepressant.15
This post hoc analysis by Taylor et al15 found that the relative risk for death or recurrent myocardial infarction after the trial's 29-month follow-up was most notably reduced in patients taking SSRIs compared to those taking any other antidepressant or no antidepressant. Furthermore, the risk for all-cause mortality was lower in this group.15 However, it is important to note that this was a post hoc analysis and, as such, is limited in its conclusions. Secondly, most participants taking the SSRI were also undergoing CBT, which may have contributed to the decrease in morbidity and mortality rates in the SSRI group.15
Adverse Patient Response to SSRI Therapy
Sertraline was associated with higher incidences of nausea (19.9% vs 10.9%) and diarrhea (18.8% vs 7.7%) than placebo.13 Citalopram was also associated with higher incidences of diarrhea (49.3% vs 23.9%), dizziness (48.6% vs 30.3%), somnolence (43.7% vs 25.4%), sweating (39.4% vs 23.9%), palpitations (25.4% vs 14.8%), and decreased libido/sexual dysfunction (21.1% vs 7%) compared to placebo.11 In addition, SSRIs may inhibit isoenzymes in the cytochrome P-450 system, altering the metabolism and increasing the drug levels of many commonly prescribed medications (Table 3).
Summary and Implications for Practitioners
These 6 studies have noted some potential benefits and some drawbacks with SSRI use in patients with ACS. However, several limitations of these studies exist and make it somewhat complicated to compare the findings. Four studies included only patients with major depression,5,11-13 whereas the remaining 2 studies14,15 also included patients with minor depression, which could account for variations in the findings. Further differences between the studies include the proximity of the ACS and the intervention. One study11 included some participants more than 2 years after their ACS, whereas other studies included those within 1 month of the event,5,13-15 and the length of time from the coronary event and length of time with depression could influence the participants' response to therapy. Furthermore, the studies were of short duration, so long-term data remain limited. Only 4 of the 6 studies were primary research articles,11-14 and of those, only 3 studies11-13 randomized participants to SSRI therapy. Of those studies, all noted positive findings with SSRI treatment.
All 3 studies that evaluated the safety of SSRIs found them to be safe for use in the studied populations.11-13 These studies suggest positive outcomes from the use of SSRIs in depressed patients with post-ACS. The greatest benefit from SSRIs on post-ACS depression ratings appears to be in patients who are recurrently and more severely depressed than those patients with mild or first-time depression.11,13 Further benefits from SSRIs appear to be on subjective quality of life ratings and on lowering morbidity and mortality. However, caution must be taken when prescribing these medications. Selective serotonin reuptake inhibitors may cause various discomforting adverse effects (see Table 4) and may cause significant drug-drug interactions. The risk-to-benefit ratio must be independently calculated for each patient.
The Institute for Clinical Systems Improvement supports the use of an SSRI and/or psychotherapy for the treatment of depression in cardiac patients (including patients with post-ACS).18 Although psychotherapy (treatment of emotional and mental disorders by psychological means, including CBT and IPT) appears to have some benefit on depression scores, according to 2 recent studies, it does not appear to improve overall morbidity and mortality rates.11,14 Selective serotonin reuptake inhibitors do show some favorable movement toward decreasing morbidity and mortality.11,14,18 Despite the promise of SSRIs for patients with post-ACS, the lack of data does limit their more widespread use. The need for large, randomized control trials is certainly evident.
Although the literature on the use of SSRIs in the post-ACS population remains encouraging, large, randomized control trials are still necessary to validate the supposition that SSRIs are associated with decreased rates of morbidity and mortality. Furthermore, before SSRIs can become first-line treatment for depression in patients with post-ACS, the benefits of using pharmacologic therapy with possible adverse effects and drug interactions must outweigh the safer avenue of nonpharmacologic treatment. Large, randomized control trials in patients with post-ACS that compare the benefits of pharmacologic therapy, specifically SSRIs, to that of nonpharmacologic therapy (such as psychotherapy), as well as studies that combine SSRI and psychotherapy, are still recommended. If SSRIs do demonstrate a statistically significant decrease in morbidity and mortality in depressed patients with post-ACS, further studies exploring the properties of serotonin and SSRIs may be warranted to investigate the possible cardiac benefits that SSRIs may be able to provide for all patients with post-ACS.19
The author thanks Patricia Griffith, MSN, CRNP, of the University of Pennsylvania School of Nursing for reviewing this article.
2. Murray CJ, Lopez A. Alternative projections of mortality and disability by cause 1990-2020: global burden of disease study. Lancet
3. Jiang W, Krishnan RR, O'Connor CM. Depression and heart disease: evidence of a link, and its therapeutic implications. CNS Drugs
4. Bush DE, Ziegelstein RC, Tayback M, et al. Even minimal symptoms of depression increase mortality risk after acute myocardial infarction. Am J Cardiol
5. Swenson JR, O'Connor CM, Barton D. Influence of depression and effect of treatment with sertraline on quality of life after hospitalization for acute coronary syndrome. Am J Cardiol
6. Glassman AH, Roose SP, Bigger Jr JT. The safety of tricyclic antidepressants in cardiac patients: risk-benefit reconsidered. JAMA
7. Cohen HW, Gibson G, Alderman MH. Excess risk of myocardial infarction in patients treated with antidepressant medications: association with use of tricyclic agents. Am J Med
8. Parissis JT, Fountoulaki K, Filippatos G, Adamopoulos S, Paraskevaidis I, Kremastinos D. Depression in coronary artery disease: novel pathophysiologic mechanisms and therapeutic implications. Int J Cardiol
9. Peterson AM, Natale F. In Depressive Disorder: Arcangelo VP, Peterson AM, eds. Pharmacotherapeutics for Advanced Practice: A Practical Approach
. 2nd ed. Philadelphia, PA: Lipincott Williams & Wilkins; 2006:609-621.
10. Maurer-Spurej E. Serotonin reuptake inhibitors and cardiovascular diseases: a platelet connection. Cell Mol Life Sci
11. Lesperance F, Frasure-Smith N, Laliberte M, 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
12. 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
13. Glassman AH, O'Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA
14. Writing Committee for the ENRICHD Investigators. 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
15. Taylor CB, Youngblood ME, Catellier D, et al. Effects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction. Arch Gen Psychiatry
16. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry
17. Beck AT, Ward CH, Mendelson M, Mock J, Eubaugh J. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:53-63.
19. Jiang W, Krishnan RR. Should selective serotonin reuptake inhibitors be prescribed to all patients with ischemic heart disease? Curr Psychiatry Rep
© 2008 Lippincott Williams & Wilkins, Inc.