Cardiovascular Effects of Selective Serotonin Reuptake Inhibitors and OtherNovel 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 novelantidepressants and their possible interactions with cardiovascular medications. The literature was reviewedthrough Medline 1980-2001. Materials were located by using terms such as SSRIs, individual names of novelantidepressants matched with terms like cardiovascular effects, cardiovascular diseases, cardiovascular riskfactors, etc. Drug compendiums from 1998-2001 and some psychopharmacology texts were also used. Thearticle focuses on the cardiovascular effects of the newer antidepressants, their use in patients withcardiovascular disease, and interactions with various commonly used cardiovascular drugs.

Introduction

Depression is the most common psychiatric illness and is frequently present in patients with cardiovasculardisease. Recently, depression has been shown to increase the cardiovascular mortality in patients with orwithout cardiac disease.[1-6] In one recent study, the diagnosis of depression increased the risk of myocardialinfarction >4-fold when controlled for both medical risk factors and other psychiatric diagnoses.[4] There ismounting evidence that depression itself may be an independent risk factor for cardiovascular disease.[1-6] anda predictor of death in survivors of acute myocardial infarction.[1] It has not yet been determined whethertreating depression reverses depression as a risk factor for cardiovascular diseases. In a most recent study of653 cases of smokers who had myocardial infarction, 143 patients were on fluoxetine, fluvoxamine, paroxetineor 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% oftreated 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 werecaused by a relative deficiency in the brain of the neurotransmitters norepinephrine (NE), serotonin (5HT), ordopamine.[9] These medications were thought to act by blocking the reuptake of these neurotransmitters inthe brain, thus potentiating their action. More recently, the "receptor sensitivity hypothesis"[10] implies thatdepression is caused by abnormal regulation of monoamine receptor sensitivity. The "dysregulation hypothesis"[11] suggests that depression is caused by a dysregulation of homeostatic mechanisms controllingneurotransmitter receptor functioning. Taking center stage as the neurobiological explanation for depression isthe monoamine hypothesis of gene statement. This hypothesis suggests that there is no clear evidence ofmonoamine deficiency or deficits in monoamine receptors. Instead, it focuses on the facts that there is apseudo-monoamine deficiency due to deficiency in signal transduction from the monoamine neurotransmitterto its postsynaptic neuron. The presumed deficit is in the second messenger systems, which lead to theformation of intracellular transcription factors that control gene statement.[12] The newest hypothesiscontributing 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 hypothesespropose that antidepressants work by reversing an actual or functional monoamine-deficit state. The

propose that antidepressants work by reversing an actual or functional monoamine-deficit state. Theinteractions between SSRIs and cardiovascular drugs and newer antidepressants and cardiovascular drugs arereviewed in Table 1 and Table 2, respectively. Possible cardiac toxicities of various antidepressants arereviewed 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 tricyclicantidepressants, which block the reuptake of 5HT and NE, SSRIs are pure 5HT reuptake blockers and havelittle effect on other neurotransmitters. These drugs have little or no anticholinergic, antihistaminic or -adrenergic effects. The SSRIs have virtually eclipsed the other major antidepressants because of theirrelatively favorable cardiac side-effect profile and comparable clinical efficacy in the milder forms ofdepression.[13] Although there have been some conflicting reports that these agents are less effective than thetricyclic antidepressants for severe depression, they appear less likely to unmask a manic phase in patientswith bipolar disorder.[14] The major side effects of the SSRIs are caused by stimulation of certain knownreceptors, which include nausea, (5HT3 stimulation in hypothalamus and mid brain), diarrhea (5HT3 and 5HT4receptors 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 mayinhibit orgasm and ejaculation).[16] SSRIs are remarkably less likely than tricyclic antidepressants to be lifethreatening 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 cardiovasculardisease.[19]

The cardiovascular effects of SSRIs in general are very moderate slowing of pulse rate, little or no effect oneither 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 vasoconstrictiveeffects on damaged endothelium.[21] The detailed cardiovascular effects of each agent are discussedindividually. 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 amixture of an S and an R enantiomer. It is the latest of the SSRIs approved for the treatment of depression. Itwas used for many years in Europe before it was approved in the United States. Unlike other SSRIs, it isrelatively selective for 5HT reuptake inhibition.[12] It has low or no affinity for 5HT1A, 5HT2A, D1, D2, 1, 2,-adrenergic, H1, muscarinic or cholinergic receptors.

Although citalopram does not cause significant QTc changes or ECG changes, it can cause some decrease in theheart 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 1% of the cases.[24]

Infrequent side effects may be hypertension bradycardia, myocardial infarction, cerebrovascular accident andmyocardial infarction. Rare incidents of transient ischemic attacks, phlebitis and atrial fibrillation, cardiacarrest, and bundle branch block have been described, the incidences of which are <1 in 1,000. It has not beenstudied systematically in patients having cardiovascular disease. There has been only one report of deathfollowing 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

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

Fluoxetine

Fluoxetine hydrochloride is also chemically unrelated to tricyctic antidepressants. In addition to its 5HTreuptake inhibitor action, it possesses some NE reuptake and 5HT2c agonist action.[12] It is the first SSRIapproved 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 arterydisease patients, which may have an anginal effect.[21] Roose et al[27] showed that fluoxetine seemed to be abenign treatment of depressed patients with cardiovascular diseases. There are negligible effects on bothresting and postural blood pressure. There was no effect on the blood pressure, nor did it have orthostatichypotensive effect even in patients with impaired left ventricular function. The agent did not seem to affectconduction, even in patients with preexisting conduction disease. There is one report of fluoxetine causingatrial fibrillation in an elderly patient.[28] Fluoxetine has been associated with decreased plasma glucose levelsand 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 ofthe cytochrome P450 2D6 iso-enzyme. In the largest series of overdoses cases, the authors in the studyreported incidents of sinus tachycardia, trigeminy, and junctional rhythms on doses as high as 1500 mg offluoxetine alone.[30] Despite these case reports, fluoxetine has very few documented cardiovascular effects.Out of 15,000,000 estimated treatment cases, there were only 5000 reports of cardiovascular effects ofany kind, ranging from ECG abnormality, to thrombophlebitis, and cardiovascular events, which may or maynot have been the direct effect of fluoxetine. Thus, the incidence of adverse cardiovascular events withfluoxetine 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 offluoxetine. Weekly dosing of fluoxetine appears to be well tolerated and is possibly as effective as daily dosingin the treatment of depression.[32] Adherence with once-weekly fluoxetine was superior to that of once-dailydose in one study.[33] Before starting the weekly fluoxetine, the patient should be stabilized on 20 mg of dailyfluoxetine. Once daily fluoxetine is working and symptoms have been improved, patients may be switched tothe weekly form. The weekly dose is recommended to be initiated 7 days after the last 20 mg daily dose offluoxetine.

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 notclear. This agent was approved in 1995 for obsessive-compulsive disorder.

There are no significant EKG changes reported with fluvoxamine except some ST segment changes, theoccurrence 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 1% 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

In a study of patients who had overdosed on fluvoxamine, only 15/310 developed sinus bradycardia.[34] It hasnot been extensively studied for its cardiovascular effects or in patients with concomitant cardiac disease. Likeother SSRIs, it seems to be relatively cardio-safe.

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

Paroxetine

Paroxetine is an SSRI, which is unrelated to other tricyclics and tetracyclics. It possessesmuscarinic/cholinergic antagonist actions, norepinephrine reuptake inhibition (NRI), in addition to its 5HTreuptake inhibition properties. It has little affinity for 5HT1, 5HT2, H1, D2, -adrenergic, -1 or -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 clinicaltrials, tachycardia, hypertension and syncope are described in 1% of the population. Infrequent side effectsinclude bradycardia and hypotension. Vasodilation is reported with a frequency of 4%. Hypertension is reportedby 1% of patients, whereas hypotension is seen in <1% of the cases.[24] Thrombophlebitis and vascularheadache are listed as rare side effects. Direct cardiac effects, which are described as rare, are congestiveheart failure, myocardial infarction, and angina pectoris.[24]

Like fluoxetine, study of this agent in patients with cardiovascular disease demonstrated that paroxetine wasassociated with a low incidence of adverse effects.[36] In the same study there was mild bradycardia, whichdisappeared later during the treatment. Paroxetine does not have any clinically sustained effect on the heartrate, diastolic, systolic, supine or standing blood pressure, cardiac conduction, or ventricular ectopic activity. Itdoes 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 andsigma actions, in addition to SRI. It does not have any significant affinity for adrenergic ( -1, -2, ),cholinergic, -aminobutyric acid, dopaminergic (DA), histaminergic (H1), serotonergic (5HT1A, 5HT1B, 5HT1C)or benzodiazepine. Sertraline is approved for depression, panic disorder, obsessive-compulsive disorder andposttraumatic stress disorder. Sertraline is an SSRI, which has less effect on cytochrome P450 system than theother members of the SSRI class. A "serotonin syndrome" has been described in overdose with sertraline andother SRRIs as characterized by tachycardia, coma, hypertension, hallucinations, tremor, skin flushing andhyperthermia.[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, cerebrovascularaccidents or aggravation of hypertension. Direct cardiac effects include 1% 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 significanteffect on heart rate, supine or standing systolic or diastolic blood pressure. Sertraline is currently being studiedto see if treatment of depression in patients with cardiovascular disease reduces the risk of cardiovascularevents. If this turns out to be the case, cardiologists may soon be treating depression with antidepressants asa primary cardiovascular risk reduction strategy.[40]

Venlafaxine

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

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

In comparison to placebo, the conduction abnormalities of venlafaxine did not differ from placebo.[24] There isa 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 bloodpressure is statistically significant in doses higher than 300 mg/d.[45] In placebo-controlled studies, a clinicallysignificant 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 6weeks of treatment with doses above 300 mg/day.[46]

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

Bupropion

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

Bupropion also has an appetite-suppressant action. It is contraindicated in patients with active bulimia.[47] Itcan also lower the seizure threshold, which is why there is a relative contraindication to its use in patients withseizure 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 hasshown 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 problemswith 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 areinfrequently 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 smokingcessation.[49] When used as either an antidepressant or anti-smoking agent and combined with a nicotinetransdermal system, the incidence of hypertension is increased to as high as 6.1%.[24] Therefore, bloodpressure should be monitored carefully if both bupropion and nicotine replacement strategies are usedsimultaneously.

Bupropion's combined cardiac safety and its effectiveness as both an antidepressant and anti-smoking agentmakes this medication unique among all the antidepressants. If a few more studies confirm this, bupropion

makes this medication unique among all the antidepressants. If a few more studies confirm this, bupropioncould become the preferred choice among cardiologists for patients with cardiovascular disease and forpatients with cardiac risk factors.

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

Trazodone and Nefazodone

Trazodone and nefazodone have different structures from the tricyclic and monoamine oxidase inhibitorantidepressant drugs. These agents are sibling compounds, which come from the same class ofantidepressants, sometimes called 5HT 2A antagonist/reuptake inhibitors. Trazodone acts by a potent blockadeof serotonin 2A (5HT2A) receptors, combined with less potent SRI action. It also has antihistamine propertiesand -1 antagonist action. Trazodone lacks the quinidine-like properties of the tricyclic antidepressants andlacks major effects on cardiac conduction. However, it can cause rare ventricular ectopy, including ventriculartachycardia.[50] The major known cardiovascular toxicity with trazodone is postural hypotension, which may beassociated with syncope. The risk of hypotension can be less if the drug is taken with meals. Trazodone cancause priapism, which requires discontinuation of the drug and emergency intervention.[9, 51] It was thedevelopment 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 alsohas weak NRI as well as weak -1 adrenergic blocking properties. It does not have significant affinity for -1and adrenergic, 5HT1A, cholinergic, DA or benzodiazepine activity. It has been found to have a lowerfrequency of orthostatic hypotension and priapism than trazodone.[52] It has less anticholinergic and -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 betweenplacebo and nefazodone for bradycardia, the clinical significance of which is not clear. Ventricular systoles areinfrequent, whereas the occurrence of atrioventricular block is <1 per 1000. Hypertension and syncope areinfrequent. 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 associatedcardiotoxicity, their combination should be avoided. Coadministration of cisapride, astemizole, and pimozideare also contraindicated because of the risk of QTc prolongation. Digoxin levels should also be monitored ifnefazodone is taken concurrently, because both drugs are protein-bound. Nefazodone does not seem toinfluence warfarin levels.[54] Nefazodone recently received a black box warning from the FDA about the risk ofhepatotoxicity.

Mirtazapine

Mirtazapine has a tetracyclic chemical structure unrelated to SSRIs, tricyclics, or monoamine oxidaseinhibitors. The mechanism of action is not 5HT reuptake blockade like SSRIs,[55] but an antagonist action atcentral presynaptic -adrenergic inhibitory autoreceptors and hetero-receptors, which increases the centralnoradrenergic and 5HTergic activity. It is a potent antagonist of 5HT2 and 5HT3 receptors and has nosignificant affinity for 5HT1A and 5HT1B receptors.[24]

Mirtazapine is not associated with clinically significant ECG abnormalities. The infrequent side effects includeventricular extra systole and bradycardia; atrial fibrillation is rare. Direct cardiac effects include <1% incidenceof myocardial infarction, angina pectoris; rarely, left heart failure has been reported. The drug blocks H1receptor, which explains its prominent sedative effects and probably the weight gain. It has a moderateperipheral -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 byhypotension.

There is some evidence that the agent has a faster onset of action as compared with other selective SRIs.[55]

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, whichcan be explained by its mild anticholinergic activity. It is a relatively newer antidepressant and has not beenstudied 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 forrelease. Reboxetine has no effect on DA or 5HT reuptake. It has been shown to be more effective in relievingthe impaired social functioning and targets symptoms as tiredness, fatigue, psychomotor retardation andapathy. It has negligible affinity for adrenergic, histaminergic, muscurinic, DA, or serotonergic receptors. Drymouth, insomnia, sweating and constipation are commonly reported side effects, although, unlike the tricyclicantidepressants, 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 notsignificantly 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 cardiovasculardiseases. These medications are considered to be relatively cardio-safe, but they are not devoid ofcardiovascular effects and drug interactions. Therefore, cardiologists should be more aware of the possiblecardiovascular effects and interactions of these antidepressants. Cardiac monitoring is required for patientssuffering from cardiovascular diseases receiving antidepressants. It is helpful to build a knowledge base aboutthe effects of antidepressants, as their use is becoming more common. Cardiologists can also assist in helpingin 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 ofNeuroscience, University of North Dakota School of Medicine and Health Sciences, Fergus Falls, MN 56537;†New York Medical College/Westchester Medical Center, Valhalla, NY