Special Feature
Depression and Cardiovascular Disease: A Key Link?
By Michael F. Barber, PharmD
Cardiovascular disease (cvd) is the leading cause of death and serious illness in the United States. The management of patients with CVD usually involves the identification and subsequent treatment of alterable risk factors for myocardial infarction (MI). However, recent research has identified a new possible risk factor, one that is often overlooked in primary care practices: depression. Depressive disorders may be present in nearly 40% of patients who have coronary heart disease and 45% in those who recently experienced an MI.1 Further, a review of epidemiological evidence suggests that depression is an independent risk factor in CVD.2
This is based on striking evidence that associates the presence of depression with several markers of the development and progression of CVD. For instance, patients with depression exhibit markers of sympathoadrenal hyperactivity, such as elevated concentrations of corticotropin-releasing factor, resulting in elevated cortisol levels, increasing the risk for development and progression of CVD.3 Also, patients with depression show diminished heart rate variability, which has been implicated as a risk factor for mortality in patients after MI.4 Further, psychological stress (such as that present in depressed patients) increases the risk of life-threatening arrhythmias.5 Depressed patients also exhibit enhanced platelet activation, which can cause or worsen CVD.6 Thus, the presence of depression may be viewed as equally important as dyslipidemia with respect to CVD. Depression has been shown to be roughly equivalent to left ventricular dysfunction as a predictor of increased mortality within six and 18 months of an MI.7,8
The relationship between depression and CVD has long been recognized. However, the usual assumption is that patients are depressed or sad because they have cardiac disease. Such an assumption fails to recognize that depression is largely biologically based. Further, although it is conceivable that depression takes place in genetically vulnerable individuals in the context of a stressor (presence of a life-threatening disease), there are intriguing data that suggests a common pathophysiologic link between depression and CVD. For example, both disease states have been associated with a deficiency in omega-3 fatty acids, suggesting that the two may be etiologically linked, rather than depression resulting from CVD.9 Unquestionably, the evidence to date necessitates the screening for depression in patients with CVD. After the diagnosis of depression is made, the clinician should consider initiating an antidepressant. The selection of an appropriate agent should be done on an individual basis, keeping in mind some general considerations regarding antidepressants and their adverse effects in patients with CVD. It is well established that tricyclic antidepressants (TCAs) have significant cardiovascular side effects. The two main cardiovascular effects of TCAs are arrhythmias and orthostatic hypotension. There are numerous published cases, several of which have been fatal, of torsades de pointes associated with the use of TCAs. Selective serotonin reuptake inhibitors (SSRIs) have largely replaced TCAs as front-line therapy for the treatment of depression as a result of their relatively benign side effects profile and more favorable safety profile in acute overdose situations. In addition, SSRIs have very few cardiovascular effects, making them more attractive for use in patients with CVD.
SSRIs and TCAs with CVD
There have been at least two reports of direct comparisons of cardiovascular effects of SSRIs and TCAs in patients with CVD. Roose et al.10 found no conduction disturbances, arrhythmias, or orthostatic hypotension and only a 4% rate of cardiovascular effects (slight decreases on heart rate, increases in supine systolic pressure, and increases in ejection fraction) in fluoxetine-treated patients (n = 27), versus a 20% incidence of cardiovascular effects (increased heart rate and orthostatic hypotension) in nortriptyline-treated patients (n = 60). In a separate study, Roose et al.11 found a 2% occurrence of adverse cardiac events in 41 patients treated with paroxetine versus 18% of 40 patients treated with nortriptyline. Sertraline has also been shown to be relatively devoid of adverse cardiovascular effects in an open trial of depressed patients who experienced an MI within the previous 30 days.12 While these data are suggestive that SSRIs are safer to use in patients with CVD, it should be noted that these studies were small, open, and of relatively short duration. Bupropion (n = 58) was also found to be relatively safe with respect to cardiovascular side effects in depressed outpatients without CVD when compared to nortriptyline (n = 57), suggesting that it may be appropriate for patients with CVD.13 Both groups had some orthostatic hypotension, but only the nortriptyline-treated group showed a slowing of cardiac conduction. Presently, there is little known about the safety of venlafaxine or mirtazapine in this population. Venlafaxine causes dose-dependent increases in supine diastolic blood pressure, which may be significant only at doses above 300 mg/d.14 Mirtazapine is relatively devoid of direct cardiovascular effects but has been associated with increases in lipid levels.15 Consideration must also be given to the potential for an antidepressant to cause a clinically significant drug interaction with a patient’s current medication. The most important drug interactions typically occur with "narrow therapeutic index" drugs.
Inhibition of Oxidative Metabolism
One of the most important mechanisms of clinically significant drug interactions caused by antidepressants involves the inhibition of oxidative metabolism of other drugs mediated through the cytochrome P450 (CYP) system. Within this enzyme system, the four most common isoenzymes which mediate antidepressant drug interactions are CYP2D6, CYP3A4, CYP1A2, and CYP2C.16 Many medications commonly prescribed to patients with CVD are metabolized by one or more of these enzymes. Lipophilic beta blockers such as metoprolol are metabolized by CYP2D6, which can be inhibited by most SSRIs, most notably paroxetine and fluoxetine. Also notable is the fact that beta blockers do not necessarily cause depression. 17 Warfarin is metabolized by CYP2C and CYP1A2 and is inhibited by fluoxetine, fluvoxamine, and to a lesser extent, sertraline. Paroxetine and fluoxetine have also been reported to increase the likelihood of bleeding without an increase in clotting times, perhaps due to a serotonin-mediated decrease in platelet adherence.18 This effect could theoretically take place with the other SSRIs as well. Inhibition of CYP3A4 by nefazodone, fluvoxamine, and to a lesser extent fluoxetine and sertraline may result in increased concentrations of calcium channel blockers as well as the antilipemic drug lovastatin, which may subsequently cause rhabdomyolysis.
Summary
In summary, given the effect of depression on patients with CVD, it is important to screen for and treat depression in this population. Despite the need for more long-term data, it is apparent that the newer antidepressants such as the SSRIs are relatively safer to use than TCAs with respect to CVD. Despite the improved safety, newer antidepressants may cause clinically significant drug interactions with medications commonly used in patients with CVD. Thus, the selection of an antidepressant should be done on an individual basis and with careful discrimination.
References
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