Treatment of Mood Disorders: Specific Medical Illnesses
Exciting progress has been made involving the relationship of coronary artery disease (CAD) and depression. Among patients with CAD, the prevalence of major depression has been shown to be at least threefold higher than that of noncardiac patients. Numerous studies have consistently demonstrated a significant difference in cardiac events and mortality, despite evidence that depression does not increase the severity of the anatomic disease. Approximately 20%-40% of patients with CAD have been shown to have depressive symptoms, and in this group of patients, the mortality rate 6 months after MI was five times higher than that of nondepressed patients with CAD. Further study revealed that 30% of patients with depressive symptoms (with or without meeting criteria for major depression) had a higher mortality rate over 18 months of follow-up. This difference in mortality rate remained an independent variable even when controlling for decreased left ventricular ejection fraction and previous MI (adjusted hazard ratio 4.29). Barefoot et al. (1989) showed that depressed patients with CAD had a risk of sudden cardiac death 84% higher than nondepressed patients with CAD. The data clearly demonstrate the significant role that depression plays in CAD, but the mechanism of this contribution is still based on theory. It is known that depression leads to the dysregulation of the sympathetic nervous system and of the HPA axis. These changes have been found to result in elevations in plasma and urinary cortisol, catecholamines, and their metabolites. Not surprisingly, these neuroendocrine changes have been implicated in the evolution of coronary disease. Platelet aggregation has also been found to be altered in patients with depressive illness. With increased platelet reactivity and aggregation, the myocardial ischemic threshold may be lowered and potentially increase anginal symptoms. This increase in platelet aggregation could also lead to increased thrombus formation and increased risk for infarction. Studies are currently under way to determine how the biochemical changes that occur with depression contribute to the pathogenesis of CAD.
From a biochemical and physiological standpoint, much of this information is internally consistent. Increased platelet activation and exaggerated platelet reactivity have been found in unmedicated patients with major depressive illness. Circulating platelet factor 4 and β-thromboglobulin, markers of platelet activation, are lower in nondepressed patients without ischemic heart disease than in nondepressed patients with ischemic heart disease. These markers are also found at much higher levels in patients who are both depressed and have depressive disorders. Depression has been associated with increased platelet serotonin receptor density, and platelet activation is lower in nondepressed patients without ischemic heart disease than in nondepressed patients with ischemic heart disease. These markers are also found in higher levels in patients who have depressive symptoms. Although the investigators were unable to find a direct correlation between SSRIs and thrombus formation, they speculated that serotonin may play an important role in the pathogenesis not only of CAD but also of MI.
Serotonin and the SSRI class of medications could play a significant role in the future treatment of depression and CAD. Serotonin’s action may involve not simply the reduction of depressive features but also the alteration of the function of platelets and aggregation. Serotonin is stored in platelets and, when released, stimulates thrombus formation. Thus, inhibition of this mechanism may reduce thrombus formation. An attempt to clarify this issue was made in an open-label trial of the use of sertraline for major depression after acute MI. The results with the 26 patients studied revealed significant improvement of mood in 71% of patients. In addition, relatively few serious adverse events and no significant changes in heart rate, blood pressure, cardiac conduction, or left ventricular ejection fraction occurred. Another small study by Roose and colleagues (1998) used fluoxetine in 27 patients over 7 weeks and revealed no effect on cardiac conduction, ventricular arrhythmia, or orthostatic blood pressure. Overall, only 4% of the patients studied had adverse cardiovascular effects, including decrease in heart rate and increase in systolic blood pressure. Roose et al. (1998) carried out a prospective double-blind, placebo-controlled study comparing the safety and efficacy of paroxetine with that of nortriptyline in depressed patients with ischemic heart disease. The study was a multisite project and involved 81 patients who were randomly selected to use either paroxetine or nortriptyline. Both paroxetine and nortriptyline were found to be effective in the treatment of depressive illness in patients with ischemic heart disease. Paroxetine was not found to demonstrate a significant effect on heart rate, blood pressure, conduction intervals, or ventricular arrhythmia. Nortriptyline was found to induce a statistically significant (11%) increase in heart rate but was not found to cause additional ventricular ectopy or prolongation of cardiac PR, QRS, or QTc intervals. The mean dose of the medication at the end of the study was approximately 22 mg for paroxetine and 74 mg for nortriptyline.
Although these studies demonstrate the safety of SSRIs in patients with cardiovascular illness, several limitations exist. First, fewer than 150 patients collectively with both cardiovascular disease and depression have been studied; second, fewer than 30 of these patients were enrolled after MI. Clearly the preliminary data collected suggest a possible improvement in the care of the depressed cardiovascular patient, which has helped motivate the design and funding of a major multicenter trial of sertraline in heart disease and MI (SADHART—Sertraline in Depression Post-Acute Myocardial Infarction).
The use of MAOIs and other newer antidepressants in cardiac patients is less documented in the psychiatric literature than the use of other antidepressants in this population. Bupropion, nefazodone, and venlafaxine could be considered for treatment of depression in patients with cardiovascular illness. Roose and colleagues (1991) studied the cardiovascular effects of bupropion in a small study of 36 inpatients with DSM-III (American Psychiatric Association 1980) major depression and preexisting left ventricular impairment, ventricular arrhythmia, and/or evidence of a conduction delay problem. No cardiac medications were changed in any of the enrolled patients, and they received bupropion for 3 weeks at a mean dosage of 442 mg/day. It was noted that the bupropion did lead to an increase in supine blood pressure, but no evidence was found of conduction complications, including worsening arrhythmias, change in heart rate, or orthostatic hypotension. Of note, more than 14% of the patients dropped out of the study as a result of drug side effects. Both bupropion and venlafaxine have been associated with blood pressure elevations at higher dosages, although blood pressure elevations are reportedly less in the newer long-acting form of venlafaxine. Nefazodone and fluvoxamine are contraindicated in use with other CYP3A4 active compounds, including quinidine and lidocaine. MAOIs have only minimal effects on cardiac activity. They may produce a slight decrease in heart rate and also can produce a shortening of the QT interval, but rarely are these changes of any clinical significance. However, the hypotensive effect of MAOIs occurs more frequently in hypertensive than in normotensive patients. Because CAD is often accompanied by hypertension, and because of the risk for increased falls and syncope in the elderly, these agents should be used with caution.
Revision date: July 4, 2011
Last revised: by Andrew G. Epstein, M.D.