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TREATMENT |
From the College of Physicians and Surgeons, Columbia University, New York, New York (S.P.R.); and Neuropsychiatry Research Clinic, New York State Psychiatric Institute, New York, New York (M.M.).
Address correspondence and reprint requests to Steven P. Roose, MD, New York State Psychiatric Institute, 1051 Riverside Drive, Unit 98, New York, NY 10032. E-mail: spr2{at}columbia.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCARDIOVASCULAR EFFECTS OF...CARDIOVASCULAR EFFECTS OF THE...NEW GENERATION ANTIDEPRESSANTSNOTESREFERENCES |
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Key Words: antidepressants • ischemic heart disease • heart rate variability • selective serotonin reuptake inhibitors • tricyclics
Abbreviations: TCA = tricyclic antidepressant; MI = myocardial infarction; IHD = ischemic heart disease; CAST = Cardiac Arrhythmia Suppression Trial; SADHART = Sertraline Antidepressant Heart Attack Randomized Trial; HRSD = Hamilton Rating Scale for Depression; SSRI = selective serotonin reuptake inhibitor.
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INTRODUCTION |
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CARDIOVASCULAR EFFECTS OF ANTIDEPRESSANTS |
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The TCAs have also been found to increase heart rate. This increase in heart rate is due to the anticholinergic effect of the TCAs, an effect that is thought to be unrelated to the antidepressant mechanism of action; the increase in heart rate is observed equally in responders and nonresponders. It is also an effect that has generally been overlooked as a source of negative long-term consequences; an increase in heart rate from 72 to 80 will neither be experienced by the patient nor give the clinician cause to take notice in the course of an acute (6- to 8-week) antidepressant trial. The increased cardiac work associated with a 10% increase in heart rate when measured over years, however, may eventually result in significant adverse events, especially in patients with preexisting cardiovascular disease.
Antiarrhythmic Effect of TCAs: Cardiac Risk Reconsidered
Because of their robust efficacy and despite their known cardiovascular effects, the TCAs were widely used even among depressed patients with heart disease. However, results from the Cardiac Arrhythmia Suppression Trial (CAST) have led to a reconsideration of the safety of tricyclics in patients with IHD.
The purpose of the CAST trials was to determine whether the treatment of post-MI ventricular irritability resulted in decreased mortality. The first study was prematurely discontinued after 2 years because of significant excess deaths associated with two of the three antiarrhythmics being tested, ecainide and flecainide (2). Since ecainide and flecainide are both Type 1C antiarrhythmics, it was hoped that this finding might not apply to the third drug in the trial, moricizine, a drug with Type 1A antiarrhythmic action. However, a second study that compared moricizine to placebo, was also prematurely discontinued when it became apparent that moricizine also induced an increase in mortality comparable to ecainide and flecainide (3).
Other studies indicate that antiarrhythmic drugs may carry a risk of increased mortality not only in patients with ventricular arrhythmias post-myocardial infarction (MI) but also in patients with a broader range of ischemic disease (4–6). A possible contributing factor to this increased mortality may be an interaction between the antiarrhythmic drug and ischemic myocardium, which results in an increased risk of ventricular fibrillation (7, 8). This interaction suggests that the risk of a Type 1 antiarrhythmic medication increases proportionately with the severity of ischemic heart disease (IHD). Given these findings, the TCAs are now considered relatively contraindicated in patients with ischemic heart disease (9).
TCAs, Heart Rate Variability, and Cardiac Mortality
The TCAs significantly affect heart rate variability and QT variability. Both decreased heart rate variability and increased QT variability have been associated with ventricular fibrillation and sudden cardiac death (10, 11).
Studies of TCAs in depressed patients with IHD indicate that TCAs decrease all heart rate variability components, including high-frequency variability, which reflects parasympathetic tone (12–14). In a study comparing nortriptyline to paroxetine in depressed patients with ischemic disease, both heart rate variability and high-frequency variability were significantly decreased in the nortriptyline-treated patients, but there was no effect on these measures in paroxetine-treated patients (15). Furthermore, other studies have demonstrated that nortriptyline significantly increases QT variability in patients with panic disorder, whereas paroxetine has no effect on any measure of heart rate variability in this patient population (16). To date, multiple studies have consistently demonstrated that tricyclics decrease all component measures of heart rate variability and increase QT variability, whereas SSRIs, including studies of paroxetine, fluoxetine, and sertraline, have shown no effect on heart rate variability measures.
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CARDIOVASCULAR EFFECTS OF THE SSRIS |
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SSRIs and Platelet Activity
SSRIs may reduce platelet aggregation. Many patients with depressive illness have dysregulation of the sympathoadrenal system as evidenced by an elevated plasma level of norepinephrine. Data suggest that increased catecholamine activity increases platelet activation and aggregation contributing to thrombus formation, and studies of both healthy depressed patients and depressed patients with IHD have documented increased platelet activation compared with nondepressed controls (18, 19). The SSRIs interfere with serotonin accumulation in platelets and SSRI treatment normalizes elevated indices of platelet activation in patients with depression and IHD. The anti-platelet effect of the SSRIs seems unrelated to an antidepressant effect and occurs in both responders and nonresponders to the medication. In a study comparing paroxetine to nortriptyline in depressed patients with IHD, baseline indices of platelet activity, specifically platelet factor 4 and beta-thyroglobulin, were elevated in patients with depression and IHD compared with patients with IHD alone or normal controls. Treatment with paroxetine normalized platelet activity. This effect occurred at low doses of paroxetine and before any discernable antidepressant effect of the medication. In contrast, although nortriptyline was a very effective antidepressant in this group of patients, there was no reduction in platelet activity in nortriptyline-treated patients. The data from the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) platelet substudy are consistent with these findings (20).
Furthermore, evidence from epidemiologic studies suggests that this anti-platelet effect of SSRIs may reduce the risk of ischemic events. In a study comparing the rate of MI in patients treated with an SSRI versus no antidepressant, the SSRI-treated patients had a significantly lower rate of MI than the non–SSRI-treated patients (21).
Fluoxetine
Several studies have documented the cardiovascular effects of fluoxetine treatment. An open-label study of fluoxetine conducted to determine the cardiovascular effects in depressed elderly patients with cardiac disease showed no adverse cardiovascular effects with fluoxetine (22). The patients in this study sample were required to have at least one of the following conditions: an ejection fraction of 
50%, 10 or more ventricular premature depolarizations per hour, and/or a QRS interval of at least 0.10 seconds. Of the 27 enrolled patients, 26% were female, 44% had a history of MI, 52% had left ventricular impairment, and 63% had conduction defects. After 2 weeks of treatment, fluoxetine increased supine systolic blood pressure from 128 mm Hg to 131 mm Hg (p = .02), decreased heart rate from 78 beats/min to 73 beats/min (p = .0002), and increased ejection fraction from 35% to 37.5% (p = .05). Fluoxetine did not prolong the PR, QRS, or QTc intervals or have any effect on ventricular arrhythmias.
Other studies have replicated these findings. A study of fluoxetine in post-MI patients revealed no decrease in cardiac function (23). A study comparing fluoxetine to pemoline and placebo in healthy control subjects also did not report significant adverse effects in both post-MI and healthy control subjects (24).
Paroxetine
A study of 81 patients compared the safety and efficacy of paroxetine to nortriptyline in depressed patients with IHD (15). Eligible patients had both depression and IHD as evidenced by previous MI, coronary artery bypass graft, angioplasty, positive stress test, or angiographic findings of coronary luminal occlusion. In the intent-to-treat analysis, 61% of paroxetine-treated and 55% of nortriptyline-treated patients were classified as in remission. Paroxetine was not associated with clinically significant sustained changes in heart rate, heart rate variability, blood pressure, or conduction intervals. In contrast, nortriptyline was associated with a clinically significant sustained increase in heart rate, decreased heart rate variability, and more serious adverse cardiac events. The sustained increase in heart rate seen with nortriptyline and reported in other studies of TCAs may be of particular significance in patients with IHD because higher heart rates are positively correlated with increased mortality rate.
The number of patients with significant adverse cardiac effects who required discontinuation from the study was greater in the nortriptyline group (7 of 40 [18%]) compared with the paroxetine group (1 of 41 [2%]; p < .03).
Sertraline
Several studies with sertraline have demonstrated a relatively benign cardiovascular profile. Studies conducted in depressed patients after MI and in broader samples of patients with IHD did not report negative effects of sertraline on cardiovascular functions or morbidity.
An open-label, pilot study was conducted to determine whether sertraline was safe and effective in depressed patients immediately after MI (25). A total of 26 patients were enrolled, 57.7% were male, and the mean age was 58 years. Sertraline did not affect heart rate or supine or standing systolic blood pressure. Of the 3 patients who had adverse events leading to withdrawal from the study, none had a cardiac event.
The recently completed SADHART study is the largest study of antidepressant treatment in patients with IHD to date (26). A total of 369 patients were randomized, 74% were post-MI, and 26% had unstable angina. The sample was 64% male, the mean age was 57 years, and the mean baseline Hamilton Rating Scale for Depression (HRSD) was 19.6. Treatment effect was evaluated in three groups of patients: 1) all randomized patients, 2) patients with recurrent depression, and 3) patients with at least two prior episodes and a baseline HRSD 
18. For all three groups, sertraline had a significantly higher response rate than placebo: group 1: 67% versus 53%, p < .01; group 2: 72% versus 51%, p < .003; group 3: 78% versus 45%, p < .004. The change in HRSD was significantly greater for sertraline only in groups 2 and 3: group 1: 8.4 versus 7.6, p = .14; group 2: 9.8 versus 7.6, p < .009; group 3 to 12.3 versus 8.9, p < .001.
Sertraline had no significant effect on left ventricular function, systolic or diastolic blood pressure, cardiac conduction intervals or ventricular premature complexes; there was no difference between sertraline compared with placebo on any cardiovascular parameter assessed. Sertraline also did not have any significant effect on measures of heart rate variability, including total variability and high-frequency variability. The most intriguing result of the study was that the incidence of severe cardiovascular adverse events (death, MI, congestive heart failure, angina, and stroke) was numerically greater in the placebo group (22.4%) compared with the sertraline group (14.5%). But this difference was not statistically different at the p = .05 level. The sample size of 369 patients randomized is by no means small by depression clinical trial standards; nonetheless, the study had limited power to detect a difference in relatively infrequently occurring events between the placebo and sertraline groups. The results extend the relative safety of the SSRIs, and sertraline in particular, to treatment in the immediate post-MI periods and support the conclusion that the SSRIs are safe and effective in the treatment of depressed patients post-MI or with unstable angina. Of note, the published data do not report the frequency of severe cardiovascular adverse events in the depression responder versus nonresponder groups treated with medication and placebo, and thus it cannot yet be determined whether the apparent improvement in cardiac morbidity and mortality in the sertraline group was associated with the resolution of depression or with the anti-platelet effect of the SSRIs as discussed previously. This is not a critical question for the clinician, however, because sertraline treatment appears relatively safe and effective independent of the mechanism by which it confers reduced morbidity and mortality.
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NEW GENERATION ANTIDEPRESSANTS |
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NOTES |
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In accordance with CME accreditation guidelines, author Steven Roose disclosed that he has received research support from and served as a consultant for Forest Lab and Wyeth. The other author of this article disclosed no real or potential conflicts of interest.
DOI:10.1097/01.psy.0000163455.43226.bf
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This article has been cited by other articles:
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  R. L. Dekker, A. R. Peden, T. A. Lennie, M. P. Schooler, and D. K. Moser Living With Depressive Symptoms: Patients With Heart Failure Am. J. Crit. Care., July 1, 2009; 18(4): 310 - 318. [Abstract] [Full Text] [PDF]
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 D. S. Sheps and A. Rozanski From Feeling Blue to Clinical Depression: Exploring the Pathogenicity of Depressive Symptoms and Their Management in Cardiac Practice Psychosom Med, May 1, 2005; 67(Supplement_1): S2 - S5. [Full Text] [PDF]
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