Cardiovascular Effects of Selective Serotonin Reuptake Inhibitors and Other Novel Antidepressants
Imran S. Khawaja, MD, Robert E. Feinstein, MD

Heart Dis 5(2):153-160, 2003. © 2003 Lippincott Williams & Wilkins

Posted 05/19/2003

Abstract and Introduction

Abstract

This paper reviews the current knowledge of cardiovascular effects of the most commonly used novel antidepressants and their possible interactions with cardiovascular medications. The literature was reviewed through Medline 1980-2001. Materials were located by using terms such as SSRIs, individual names of novel antidepressants matched with terms like cardiovascular effects, cardiovascular diseases, cardiovascular risk factors, etc. Drug compendiums from 1998-2001 and some psychopharmacology texts were also used. The article focuses on the cardiovascular effects of the newer antidepressants, their use in patients with cardiovascular disease, and interactions with various commonly used cardiovascular drugs.

Introduction

Depression is the most common psychiatric illness and is frequently present in patients with cardiovascular disease. Recently, depression has been shown to increase the cardiovascular mortality in patients with or without cardiac disease.[1-6] In one recent study, the diagnosis of depression increased the risk of myocardial infarction >4-fold when controlled for both medical risk factors and other psychiatric diagnoses.[4] There is mounting evidence that depression itself may be an independent risk factor for cardiovascular disease.[1-6] and a predictor of death in survivors of acute myocardial infarction.[1] It has not yet been determined whether treating depression reverses depression as a risk factor for cardiovascular diseases. In a most recent study of 653 cases of smokers who had myocardial infarction, 143 patients were on fluoxetine, fluvoxamine, paroxetine or sertraline. This study demonstrated a significant association between selective serotonin reuptake inhibitor (SSRI) use and lower odds of having myocardial infarction among smokers.[7]

Novel Antidepressants

The novel antidepressant medications have had a major impact on depression, relieving symptoms in 70% of treated subjects in clinical trials, compared with 30% who received placebo.[8]

The theoretical basis of antidepressant therapy was originally thought to be that depressive symptoms were caused by a relative deficiency in the brain of the neurotransmitters norepinephrine (NE), serotonin (5HT), or dopamine.[9] These medications were thought to act by blocking the reuptake of these neurotransmitters in the brain, thus potentiating their action. More recently, the "receptor sensitivity hypothesis"[10] implies that depression is caused by abnormal regulation of monoamine receptor sensitivity. The "dysregulation hypothesis"[11] suggests that depression is caused by a dysregulation of homeostatic mechanisms controlling neurotransmitter receptor functioning. Taking center stage as the neurobiological explanation for depression is the monoamine hypothesis of gene statement. This hypothesis suggests that there is no clear evidence of monoamine deficiency or deficits in monoamine receptors. Instead, it focuses on the facts that there is a pseudo-monoamine deficiency due to deficiency in signal transduction from the monoamine neurotransmitter to its postsynaptic neuron. The presumed deficit is in the second messenger systems, which lead to the formation of intracellular transcription factors that control gene statement.[12] The newest hypothesis contributing to our discovery about the nature of depression is the suggestion that neurokinins (such as substance P) may be involved in the pathophysiology of depression.[12] As a group, all of these hypotheses propose that antidepressants work by reversing an actual or functional monoamine-deficit state. The interactions between SSRIs and cardiovascular drugs and newer antidepressants and cardiovascular drugs are reviewed in Table 1 and Table 2, respectively. Possible cardiac toxicities of various antidepressants are reviewed in Table 3.

Selective Serotonin Reuptake Inhibitors

SSRIs became available in the 1980s. These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), fluvoxamine (Luvox) and the latest one, citalopram (Celexa) (Table 4). Compared with tricyclic antidepressants, which block the reuptake of 5HT and NE, SSRIs are pure 5HT reuptake blockers and have little effect on other neurotransmitters. These drugs have little or no anticholinergic, antihistaminic or alpha-adrenergic effects. The SSRIs have virtually eclipsed the other major antidepressants because of their relatively favorable cardiac side-effect profile and comparable clinical efficacy in the milder forms of depression.[13] Although there have been some conflicting reports that these agents are less effective than the tricyclic antidepressants for severe depression, they appear less likely to unmask a manic phase in patients with bipolar disorder.[14] The major side effects of the SSRIs are caused by stimulation of certain known receptors, which include nausea, (5HT3 stimulation in hypothalamus and mid brain), diarrhea (5HT3 and 5HT4 receptors in the gut), headache, agitation, and panic attacks (stimulation of 5HT2A and 5HT2C receptors). SSRIs used over the long term can also cause weight gain.[15]

SSRIs can also cause delayed ejaculation in men, and anorgasmia in women (5HT2A spinal cord receptors may inhibit orgasm and ejaculation).[16] SSRIs are remarkably less likely than tricyclic antidepressants to be life threatening when ingested in fairly high over-doses.[17] During the decade since they have been introduced, there have been only 2 well documented deaths from overdose reported in the literature: one with fluoxetine, the other with citalopram. Although these agents are said to be relatively free of major cardiovascular risks,[18] they are not totally devoid of cardiovascular effects, especially in patients suffering from cardiovascular disease.[19]

The cardiovascular effects of SSRIs in general are very moderate slowing of pulse rate, little or no effect on either resting or postural blood pressure, and little or no influence on PR, QRS, or QTc interval.[20] However, there are case reports of prolonged QTc intervals, first-degree block, and orthostatic hypotension in SSRI-treated patients.[19] These agents may cause myocardial ischemia secondary to serotonin's vasoconstrictive effects on damaged endothelium.[21] The detailed cardiovascular effects of each agent are discussed individually. The SSRIs and cardiovascular drug interactions are reviewed in Table 1.

Citalopram

Citalopram is structurally unrelated to any tricyclics, tetracyclics, or to any other antidepressants. It is a mixture of an S and an R enantiomer. It is the latest of the SSRIs approved for the treatment of depression. It was used for many years in Europe before it was approved in the United States. Unlike other SSRIs, it is relatively selective for 5HT reuptake inhibition.[12] It has low or no affinity for 5HT1A, 5HT2A, D1, D2, alpha1, alpha2, beta-adrenergic, H1, muscarinic or cholinergic receptors.

Although citalopram does not cause significant QTc changes or ECG changes, it can cause some decrease in the heart rate.[22] It has no effect on the blood pressure,[23] and it does not cause any orthostatic hypotension. Tachycardia, postural hypotension, and hypotension has been described in only approx1% of the cases.[24] Infrequent side effects may be hypertension bradycardia, myocardial infarction, cerebrovascular accident and myocardial infarction. Rare incidents of transient ischemic attacks, phlebitis and atrial fibrillation, cardiac arrest, and bundle branch block have been described, the incidences of which are <1 in 1,000. It has not been studied systematically in patients having cardiovascular disease. There has been only one report of death following overdose on citalopram alone.[20] Five of the Swedish cases were known to have ingested >1900 mg (almost 100 times the usual dose), and all of these patients had either conduction delay or seizures. Among the 18 patients in which 600-1900 mg were ingested, 6 experienced QRS widening.[20]

S-Citalopram, recently approved by the U.S. Food and Drug Administration (FDA), seems to be a more selective SSRI than the parent compound, citalopram, which is a racemic mixture. S-Citalopram is considered to be the active ingredient for mixed racemic citalopram antidepressive action. In in vitro studies, S-citalopram has a lower pharmacokinetic drug-interaction profile than the parent compound. Some recent studies also suggest that S-citalopram might be more effective than the racemic citalopram[25] and may have a better antianxiety profile as well.

Fluoxetine

Fluoxetine hydrochloride is also chemically unrelated to tricyctic antidepressants. In addition to its 5HT reuptake inhibitor action, it possesses some NE reuptake and 5HT2c agonist action.[12] It is the first SSRI approved for major depression in the United States. It is indicated in major depression, bulimia nervosa, obsessive-compulsive disorder, and premenstrual dysphoric disorder.

Fluoxetine does cause mild bradycardia,[26] more so in elderly patients with preexisting cardiac arrhythmias. There are reports of fluoxetine having vasoconstrictive effects on damaged endothelial of coronary artery disease patients, which may have an anginal effect.[21] Roose et al[27] showed that fluoxetine seemed to be a benign treatment of depressed patients with cardiovascular diseases. There are negligible effects on both resting and postural blood pressure. There was no effect on the blood pressure, nor did it have orthostatic hypotensive effect even in patients with impaired left ventricular function. The agent did not seem to affect conduction, even in patients with preexisting conduction disease. There is one report of fluoxetine causing atrial fibrillation in an elderly patient.[28] Fluoxetine has been associated with decreased plasma glucose levels and hyponatremia (seen with other selective serotonin reuptake inhibitors) in patients receiving diuretic drugs.[29]

Fluoxetine can increase the blood levels of other drugs because of its long plasma half-life[18] and inhibition of the cytochrome P450 2D6 iso-enzyme. In the largest series of overdoses cases, the authors in the study reported incidents of sinus tachycardia, trigeminy, and junctional rhythms on doses as high as 1500 mg of fluoxetine alone.[30] Despite these case reports, fluoxetine has very few documented cardiovascular effects. Out of approx15,000,000 estimated treatment cases, there were only approx5000 reports of cardiovascular effects of any kind, ranging from ECG abnormality, to thrombophlebitis, and cardiovascular events, which may or may not have been the direct effect of fluoxetine. Thus, the incidence of adverse cardiovascular events with fluoxetine is under 0.0003%.[31]

More recently, longer acting weekly fluoxetine (Prozac weekly TM) has been introduced. This is a delayed-release formulation, containing enteric-coated pellets of fluoxetine hydrochloride equivalent to 90 mg of fluoxetine. Weekly dosing of fluoxetine appears to be well tolerated and is possibly as effective as daily dosing in the treatment of depression.[32] Adherence with once-weekly fluoxetine was superior to that of once-daily dose in one study.[33] Before starting the weekly fluoxetine, the patient should be stabilized on 20 mg of daily fluoxetine. Once daily fluoxetine is working and symptoms have been improved, patients may be switched to the weekly form. The weekly dose is recommended to be initiated 7 days after the last 20 mg daily dose of fluoxetine.

Fluvoxamine

Fluvoxamine maleate belongs to a new chemical series of aralkylketones, chemically unrelated to other SSRIs. In addition to its 5HT reuptake inhibitor activity, it also possesses some sigma actions, the role of which is not clear. This agent was approved in 1995 for obsessive-compulsive disorder.

There are no significant EKG changes reported with fluvoxamine except some ST segment changes, the occurrence of which is <1%, and atrioventricular and supraventricular block which occurs <1 per 1000 cases treated.[24] Cases of hypertension, hypotension, syncope, tachycardia is described in approx1% of the patients. There are rare reports of cerebrovascular accidents, coronary artery disease, embolus, pericarditis, phlebitis, and pulmonary infarction.

In a study of patients who had overdosed on fluvoxamine, only 15/310 developed sinus bradycardia.[34] It has not been extensively studied for its cardiovascular effects or in patients with concomitant cardiac disease. Like other SSRIs, it seems to be relatively cardio-safe.

Fluvoxamine can potentiate the activity of warfarin, theophylline, and propranolol because it inhibits the hepatic P450 enzymes 1A2, 29, 2C19 and 3A4.[35] For this reason, coadministration of terfenadine, astemizole and cisapride is contraindicated.[24]

Paroxetine

Paroxetine is an SSRI, which is unrelated to other tricyclics and tetracyclics. It possesses muscarinic/cholinergic antagonist actions, norepinephrine reuptake inhibition (NRI), in addition to its 5HT reuptake inhibition properties. It has little affinity for 5HT1, 5HT2, H1, D2, beta-adrenergic, alpha-1 or alpha-2 receptors. Paroxetine is an SSRI with a short half-life, which can result in some withdrawal symptoms if stopped suddenly.

Tachycardia has been described in 12% of patients receiving this drug in one clinical trial.[35] In other clinical trials, tachycardia, hypertension and syncope are described in approx1% of the population. Infrequent side effects include bradycardia and hypotension. Vasodilation is reported with a frequency of 4%. Hypertension is reported by approx1% of patients, whereas hypotension is seen in <1% of the cases.[24] Thrombophlebitis and vascular headache are listed as rare side effects. Direct cardiac effects, which are described as rare, are congestive heart failure, myocardial infarction, and angina pectoris.[24]

Like fluoxetine, study of this agent in patients with cardiovascular disease demonstrated that paroxetine was associated with a low incidence of adverse effects.[36] In the same study there was mild bradycardia, which disappeared later during the treatment. Paroxetine does not have any clinically sustained effect on the heart rate, diastolic, systolic, supine or standing blood pressure, cardiac conduction, or ventricular ectopic activity. It does not have significant effect on ECG. Overall, paroxetine appears to have a benign cardiovascular profile.[36, 37]

Sertraline

Sertraline is chemically unrelated to tricyclics or other SSRIs. It has dopamine reuptake inhibitor action and sigma actions, in addition to SRI. It does not have any significant affinity for adrenergic (alpha-1, alpha-2, beta), cholinergic, gamma-aminobutyric acid, dopaminergic (DA), histaminergic (H1), serotonergic (5HT1A, 5HT1B, 5HT1C) or benzodiazepine. Sertraline is approved for depression, panic disorder, obsessive-compulsive disorder and posttraumatic stress disorder. Sertraline is an SSRI, which has less effect on cytochrome P450 system than the other members of the SSRI class. A "serotonin syndrome" has been described in overdose with sertraline and other SRRIs as characterized by tachycardia, coma, hypertension, hallucinations, tremor, skin flushing and hyperthermia.[35-38]

Sertraline does not have any significant effects on ECG. Tachycardia is seen in <1% of the treated population. Vascular effects of sertraline include infrequent hypertension, postural hypotension and, rarely, cerebrovascular accidents or aggravation of hypertension. Direct cardiac effects include approx1% occurrence of chest pain, palpitations, rare precardiac chest pain, and myocardial infarction.

Sertraline is an effective treatment for depressed patients with cardiovascular disease. In one study,[39] sertraline was used to treat depressed patients with cardiovascular disease, and it did not show any significant effect on heart rate, supine or standing systolic or diastolic blood pressure. Sertraline is currently being studied to see if treatment of depression in patients with cardiovascular disease reduces the risk of cardiovascular events. If this turns out to be the case, cardiologists may soon be treating depression with antidepressants as a primary cardiovascular risk reduction strategy.[40]

Venlafaxine

Venlafaxine[41, 42] is a unique antidepressant with dual mechanisms of action.[43] The agent blocks the reuptake of 5HT and NE at relevant doses in humans.[43] It also possesses weak DA reuptake properties at higher doses.[44]

Venlafaxine has no significant affinity for muscurinic/cholinergic, histaminergic (H1) or alpha-adrenergic receptors. It is approved for the treatment of depression and generalized anxiety disorder. It has a short half-life but does come in extended-release form.

In comparison to placebo, the conduction abnormalities of venlafaxine did not differ from placebo.[24] There is a mean change from baseline of corrected QT interval, which was increased relative to that of the placebo. Arrhythmias, first-degree heart block, atrioventricular block, and bundle branch block are rare effects.

The agent has a tendency to increase the blood pressure, especially in higher doses.[45] The increase in blood pressure is statistically significant in doses higher than 300 mg/d.[45] In placebo-controlled studies, a clinically significant increase in blood pressure (increase in diastolic pressure >/=15 mm to >/=105 mm from base-line) were observed in 5.5% of patients at doses above 200 mg/d; the mean increases were 7 mm of hg after 6 weeks of treatment with doses above 300 mg/day.[46]

Venlafaxine increases the heart rate significantly when compared with placebo.[24] The mean increase is 4 beats/min relative to base-line; therefore, caution should be exercised in patients whose underlying medical conditions might be compromised by increase in the heart rate (eg, patients with hyperthyroidism, heart failure, or recent myocardial infarction), particularly when higher doses are used. Other infrequent vascular effects include hypotension, peripheral vascular disorder, and thrombophlebitis. Direct cardiac effects, such as angina pectoris, have been reported in <1% of the patients, and mitral valve disease, as a complication, is rare.

Bupropion

Bupropion is an aminokene and has a unicyclic structure, which is chemically unrelated to any other antidepressants. It is structurally related to amphetamines. Its antidepressant effects appear related to NRI and dopamine reuptake inhibitory actions. It is also postulated that its DA actions account for its effectiveness as an anti-smoking agent. Unlike the SSRIs, bupropion does not produce significant sexual side effects because it lacks 5HT activity. In fact, bupropion is sometimes used effectively to treat the sexual side effects so common with SSRIs.

Bupropion also has an appetite-suppressant action. It is contraindicated in patients with active bulimia.[47] It can also lower the seizure threshold, which is why there is a relative contraindication to its use in patients with seizure disorder. This increased risk of seizures may be attenuated when the slow release preparation is used. Bupropion is also used as an augmentation agent with other SSRIs in refractory cases of depression and has shown promise in patients with ADHD because of its stimulant-like activity.

Bupropion, compared with the TCAs, is relatively cardio-safe. In one study,[48] bupropion showed no problems with conduction, contractility, or orthostatic hypotension in patients with preexisting cardiac diseases. Palpitations are reported in 2% of the cases. Postural hypotension, stroke, tachycardia and phlebitis are infrequently described, and syncope is rare. Flushing and hot flashes are seen in 1% of the treated population. Bupropion can elevate blood pressure in certain patients,[24] but does not cause any effect on heart rate.

Other than as an antidepressant, bupropion (Zyban) is also an effective agent for facilitating smoking cessation.[49] When used as either an antidepressant or anti-smoking agent and combined with a nicotine transdermal system, the incidence of hypertension is increased to as high as 6.1%.[24] Therefore, blood pressure should be monitored carefully if both bupropion and nicotine replacement strategies are used simultaneously.

Bupropion's combined cardiac safety and its effectiveness as both an antidepressant and anti-smoking agent makes this medication unique among all the antidepressants. If a few more studies confirm this, bupropion could become the preferred choice among cardiologists for patients with cardiovascular disease and for patients with cardiac risk factors.

In addition, there are studies currently underway to determine if bupropion and sertraline reduce depression as a primary risk factor for cardiovascular disease and to determine their relative safety of use in patients with existing cardiovascular disease. If this research confirms these effects, it is likely that both of these antidepressants will be the first psychotropic drugs used to reduce depression as a primary risk factor for heart disease.[40]

Trazodone and Nefazodone

Trazodone and nefazodone have different structures from the tricyclic and monoamine oxidase inhibitor antidepressant drugs. These agents are sibling compounds, which come from the same class of antidepressants, sometimes called 5HT 2A antagonist/reuptake inhibitors. Trazodone acts by a potent blockade of serotonin 2A (5HT2A) receptors, combined with less potent SRI action. It also has antihistamine properties and alpha-1 antagonist action. Trazodone lacks the quinidine-like properties of the tricyclic antidepressants and lacks major effects on cardiac conduction. However, it can cause rare ventricular ectopy, including ventricular tachycardia.[50] The major known cardiovascular toxicity with trazodone is postural hypotension, which may be associated with syncope. The risk of hypotension can be less if the drug is taken with meals. Trazodone can cause priapism, which requires discontinuation of the drug and emergency intervention.[9, 51] It was the development of priapism with trazodone that lead to the development of nefazodone.

Nefazodone also acts by blocking 5HT 2A (5HT2A) receptors, and is less potent as an SRI. In addition, it also has weak NRI as well as weak alpha-1 adrenergic blocking properties. It does not have significant affinity for alpha-1 and beta adrenergic, 5HT1A, cholinergic, DA or benzodiazepine activity. It has been found to have a lower frequency of orthostatic hypotension and priapism than trazodone.[52] It has less anticholinergic and alpha-adrenergic blocking activity. The reported frequency of orthostatic hypotension is 2.8%, bradycardia is l.5%, and no other ECG changes have been described.[53] There is statistically a significant difference between placebo and nefazodone for bradycardia, the clinical significance of which is not clear. Ventricular systoles are infrequent, whereas the occurrence of atrioventricular block is <1 per 1000. Hypertension and syncope are infrequent. Direct cardiac effects like angina pectoris is <1 in 100, whereas congestive heart failure is rare. Because nefazodone can interfere with the metabolism of terfenadine, an antihistamine with associated cardiotoxicity, their combination should be avoided. Coadministration of cisapride, astemizole, and pimozide are also contraindicated because of the risk of QTc prolongation. Digoxin levels should also be monitored if nefazodone is taken concurrently, because both drugs are protein-bound. Nefazodone does not seem to influence warfarin levels.[54] Nefazodone recently received a black box warning from the FDA about the risk of hepatotoxicity.

Mirtazapine

Mirtazapine has a tetracyclic chemical structure unrelated to SSRIs, tricyclics, or monoamine oxidase inhibitors. The mechanism of action is not 5HT reuptake blockade like SSRIs,[55] but an antagonist action at central presynaptic alpha-adrenergic inhibitory autoreceptors and hetero-receptors, which increases the central noradrenergic and 5HTergic activity. It is a potent antagonist of 5HT2 and 5HT3 receptors and has no significant affinity for 5HT1A and 5HT1B receptors.[24]

Mirtazapine is not associated with clinically significant ECG abnormalities. The infrequent side effects include ventricular extra systole and bradycardia; atrial fibrillation is rare. Direct cardiac effects include <1% incidence of myocardial infarction, angina pectoris; rarely, left heart failure has been reported. The drug blocks H1 receptor, which explains its prominent sedative effects and probably the weight gain. It has a moderate peripheral alpha-blocker activity, which can result in a 7% incidence of orthostatic hypotension. Therefore, mirtazepine should be used with caution in patients who have cardiac illness, which can be aggravated by hypotension.

There is some evidence that the agent has a faster onset of action as compared with other selective SRIs.[55] Mirtazepine does not cause any significant increase in blood pressure, but can increase the heart rate, which can be explained by its mild anticholinergic activity. It is a relatively newer antidepressant and has not been studied in patients with concomitant cardiac disease.

Reboxetine

Reboxetine is the first selective NRI (SNRI) which, as of this writing, had not yet been approved by the FDA for release. Reboxetine has no effect on DA or 5HT reuptake. It has been shown to be more effective in relieving the impaired social functioning and targets symptoms as tiredness, fatigue, psychomotor retardation and apathy. It has negligible affinity for adrenergic, histaminergic, muscurinic, DA, or serotonergic receptors. Dry mouth, insomnia, sweating and constipation are commonly reported side effects, although, unlike the tricyclic antidepressants, they tend to be mild to moderate and transient in nature.[56]

In one study, reboxetine, at a systemic exposure approximately twice the recommended dose, did not significantly affect the QTc prolongation. It does, however, increase the heart rate by 8-11 beats per minute.[57]

Conclusion

The selective SRIs and newer antidepressants are commonly used in patients with concomitant cardiovascular diseases. These medications are considered to be relatively cardio-safe, but they are not devoid of cardiovascular effects and drug interactions. Therefore, cardiologists should be more aware of the possible cardiovascular effects and interactions of these antidepressants. Cardiac monitoring is required for patients suffering from cardiovascular diseases receiving antidepressants. It is helpful to build a knowledge base about the effects of antidepressants, as their use is becoming more common. Cardiologists can also assist in helping in the process by reporting new drug-drug interactions and the toxicities of these drugs.

Tables

Table 1. Cardiovascular Drug-Drug Interactions with SSRIs

Table 2. Cardiovascular Drug-Drug Interactions with Newer Antidepressants

Table 3. Cardiac Toxicity of the Antidepressant Medications

Table 4. Selective Serotonin Reuptake Inhibitors and Newer Antidepressants

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Reprint Address

Reprints: Imran S. Khawaja, MD, 320 Western Avenue, Apt #215, Fergus Falls, MN, 56537. khimran@yahoo.com.

Imran S. Khawaja, MD* and Robert E. Feinstein, MD†

*Lakeland Mental Health Center and Department of Psychiatry and Behavioral Science, Department of Neuroscience, University of North Dakota School of Medicine and Health Sciences, Fergus Falls, MN 56537; †New York Medical College/Westchester Medical Center, Valhalla, NY