Cardiovascular effects of psychotropic drugs

Cardiovascular Effects of Psychotropic Drugs Introduction In the last 10 years it has become increasingly important for the clinical cardiologist to be knowledgeable about prescribing psychoactive medications. There are 5 major reason for this necessity: (1) Psychoactive medications are among the most commonly prescribed medications, most of which are prescribed by nonpsychiatric physicians. It is estimated that 10% to 20% of the general population are taking some form of psychoactive medications, and more than 20% of all prescriptions filled are for psychoactive medications.1 In addition, most psychoactive medications are prescribed by nonpsychiatric physicians. (2) Many psychoactive medications have prominent cardiovascular side effects, toxicities, and undesirable drug interactions with cardiovascular medicines.2 The clinical cardiologist is increasingly asked to consult about these effects. (3) Recent findings have shown that some psychiatric illnesses (eg, depression3-7 and phobic anxiety8) may have direct effects as independent cardiovascular risk factors. Other psychiatric conditions, such as generalized anxiety or alcohol abuse, may have prominent secondary effects on modifiable risk factors such as hypertension.9(4) Recent evidence suggests that some psychotropics, such as selective serotonin (5-hydroxytryptamine [5HT]) reuptake inhibitors (SSRIs), may confer a protective effect against myocardial infarction (MI) in smokers.10 Also, it may soon be determined whether antidepressants confer protections from MI in the post-MI population, in patients with existing cardiovascular diseases, and perhaps in the general population. (5) Many modifiable cardiovascular risk factors can only be successfully modified in patients when underlying psychiatric issues are addressed. For example, if a patient has a history of depression, success rates for smoking cessation are dramatically reduced.11 Use of bupropion hydrochloride (Zyban or Wellbutrin [GlaxoSmithkline, Research Triangle Park, NC]) in such a patient has the double benefit of fostering smoking cessation and preventing a recurrent depression after smoking cessation is achieved. Curr Probl Cardiol 2002;27:185-240. 0146-2806/2002/$35.00 ⫹ 0 51/1/125053 doi:10.1067/mcd.2002.125053

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In this article, commonly prescribed psychoactive drugs will be reviewed with regard to their cardiovascular effects, toxicities, and potential adverse interactions with cardioactive drugs. Drugs that are rarely prescribed by cardiologists and psychiatrists, such as barbiturates, carbamates, piperidinediones, cyclic ethers, and tertiary carbinols, will not be discussed in this chapter. Medications used by physicians to counteract adverse reactions of psychoactive medications (eg, anticholinergics) will not be reviewed.

Antipsychotics Antipsychotic drugs (Tables 1 and 2) are used in the care of those conditions that produce psychosis, such as schizophrenia, bipolar disorders, psychotic depression, delusional disorders (paranoia), schizoaffective disorders, delirium, dementias, Tourette’s syndrome, severe personality disorders, psychosis caused by general medical conditions, and substance-induced psychosis. The first antipsychotics (Table 1) are known as “neuroleptics” because they treat the positive symptoms of psychosis such as hallucination or paranoia, and simultaneously may produce significant extrapyramidal side effects (EPS) such as parkinsonism, dystonia, and akathisia, and can produce tardive dyskinesia (TD). Only 70% of patients with positive symptoms of schizophrenia12 are likely to respond to neuroleptics. Neuroleptics of phenothiazine, butyrophenones, diphenylbutylpiperidine, thiothixene, and other classes exert their primary antipsychotic action through blocking effects of the neurotransmitter dopamine at the D2 receptors. This dopamine blockade is also responsible for hyperprolactinemia, which induces neuroendocrine side effects. Neuroleptics also stimulate muscarinic, histamine, and ␣-1 receptors, which explains their predominant side-effect profiles of anticholinergic effects, sedation and weight gain, and orthostatic hypotension, respectively. Newer antipsychotics, called atypicals or novel antipsychotics12 (Table 2) treat a much broader spectrum of psychotic symptoms than older neuroleptics. This fact, combined with minimal EPS and manageable side effects, has led to these newer novel antipsychotics gradually replacing the older neuroleptics in clinical practice. Novel antipsychotics can treat, to varying degrees, all 4 symptom domains associated with psychosis that include: (1) positive symptoms (eg, hallucinations, paranoia, and thought disorder); (2) negative symptoms (eg, withdrawal, apathy, and paucity of thought); (3) mood symptoms (eg, mania, psychotic depressive symptoms, and delusions); and (4) cognitive disturbances associated with psychosis (eg, memory and disturbance in cognitive or synthetic brain Curr Probl Cardiol, May 2002

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TABLE 1. Cardiovascular effects of older antipsychotic medications* Class and agent

ECG

Phenothiazine (low potency) Chlorpromazine 1QT, blunted and (Thorazine) notched T 1AV conduction ⫹⫹, ventricular arrhythmia rare 1QTc possible torsades de pointes, quinidine effect, 1QT blunted and notched T, 1AV conduction ⫹⫹⫹⫹, ventricular arrhythmia rare Mesoridazine Quinidine effect, (Serentil) QT, blunted and notched T, 1AV conduction Phenothiazine (high potenty) Trifluoperazine 1QT, blunted and hydrochloride notched T (Stelazine) 1AV conduction ⫹ Fluphenazine 1QT, blunted and (Prolixin, notched T Permitil) 1AV conduction ⫹ Phenothiazine (mid range) Perphenazine 1QT, blunted and (Trilafon) notched T AV conduction ⫹ (rare) Butyrophenones Droperidol 1QTc, possible (Inaspine) torsades de pointes, 1AV conduction ⫹, rare ventricular arrhythmia Haloperidol Rare 1QTc, (Haldol) 1AV conduction ⫹, rare ventricular arrhythmia. With IV form 1QTc and possible torsades de pointes Thioridazine (Mellaril)

Vascular

Direct cardiac

Hypotension ⫹⫹⫹⫹

Direct depressant of contractility, mucopolysaccharide Anticholinergic ⫹⫹⫹ deposition in coronary Antiadrenergic ⫹⫹⫹⫹ arteries, cardiomegaly, rare sudden death Hypotension ⫹⫹⫹⫹ Direct depressant of Anticholinergic ⫹⫹⫹⫹ contractility, Antiadrenergic ⫹⫹⫹⫹ mucopolysaccharide deposition in arteries, cardiomegaly rare

Hypotension ⫹⫹⫹ Rare sudden death, Anticholinergic ⫹⫹⫹⫹ direct depressant Antiadrenergic ⫹⫹⫹ of contractility Hypotension ⫹ Anticholinergic ⫹ Antiadrenergic ⫹ Hypotension ⫹ Anticholinergic ⫹ Antiadrenergic ⫹

Direct depressant of contractility, rare sudden death Direct depressant of contractility, rare sudden death

Hypotension ⫹⫹ Anticholinergic ⫹⫹ Antiadrenergic ⫹

Direct depressant of contractility, rare sudden death

Hypotension ⫹⫹⫹ Anticholinergic ⫹

Direct depressant of contractility, rare sudden death

Hypotension ⫹ Hypertension ⫹ Anticholinergic ⫹

Direct depressant of contractility, rare sudden death

continued

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TABLE 1. Continued. Class and agent

ECG

Diphenylbutylpiperidine Pimozide (Orap) 1QTc, blunted and notched T wave U waves Thioxanthenes Thiothixene Rare 1QT, blunted (Navane) and notched T AV conduction ⫹, rare ventricular arrhythmia Chlorprothixene QT, blunted and notched T AV conduction ⫹⫹, ventricular arrhythmia ⫹⫹ Indolones Molindone Most benign hydrochloride (Moban) Dibenzoxazepines Loxapine Rare QT, blunted (Loxitane, and notched T Daxolin) AV conduction, rare tachycardia

Vascular Hypotension ⫹⫹ Hypertension ⫹⫹⫹ Anticholinergic ⫹⫹

Direct cardiac Sudden death

Hypotension ⫹ Anticholinergic ⫹

Hypotension ⫹⫹⫹ Cardiac arrest reported Anticholinergic ⫹⫹⫹⫹ but rare Antiadrenergic ⫹⫹

Hypotension ⫹ Anticholinergic ⫹⫹ Antiadrenergic ⫹

Least effect on cardiac contractility

Hypertension ⫹⫹ Hypotension ⫹⫹⫹ Anticholinergic ⫹⫹ Antiadrenergic ⫹⫹⫹

Slight depressant of contractility

*Effects: high, ⫹⫹⫹⫹; moderate high, ⫹⫹⫹; moderate, ⫹⫹; low, ⫹; none, 0. (Adapted from: Nurenberg JR, Frishman WH. Cardiovascular considerations with use of psychoactive medications. In: Frishman WH, Sonnenblick EH, editors. Cardiovascular pharmacotherapeutics. New York: McGraw Hill; 1997 p. 1040.)

functions that are required to learn and process information). Novel antipsychotics and clozapine have important and varying affinities for multiple biologic receptors including serotonin, dopamine, acetylcholine, histamine, and adrenergic receptors. These broader neurotransmitter effects, at multiple transmitter sites, are responsible for additional capabilities of these newer agents. In general, these newer agents do not produce significant EPS or TD, do not cause hyperprolactinemia, and may also treat neuroleptic-refractory schizophrenia. Table 2 reviews cardiac implications of newer atypical antipsychotic medications that are gaining prescribing ascendancy. The older neuroleptics, still commonly in use, are reviewed in Table 1. A summary of major drug interactions13 between antipsychotics and cardiovascular drugs is provided in Table 3. Curr Probl Cardiol, May 2002

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TABLE 2. Cardiovascular effects of newer antipsychotic medications* Class and agent

ECG

Clozapine (Clozaril)

Vascular

Direct cardiac

Frequent: tachycardia 25% ECG changes: STsegment elevations mimicking ischemic changes, ST depression, nonspecific T-wave changes Infrequent: 1QTc, atrial fibrillation, ventricular extrasystoles Risperidone Frequent: tachycardia 5% (Risperdal) Infrequent: palpitations, AV block, 1QTc Rare: Ventricular tchycardia and extrasystoles, premature atrial contractions, Twave inversion, STdepression Olanzapine Frequent: tachycardia 3% (Zyprexia) Infrequent: bradycardia, palpitations, ventricular extrasystoles Rare: 1QTc, atrial fibrillation

Frequent: Chest pain/ Frequent: Orthostatic angina 1% hypotension 9%, Rare: Cardiac arrest, hypertension 4%. sudden death, MI, Infrequent: Periorbital CHF, allergic edema, deep vein myocarditis, thrombosis, pulmonary pericarditis, embolisms cardiomyopathy Rare: transient ischemic attack

Quetiapine Frequent: tachycardia 7% (Seroquel) palpitations Infrequent: 1QTc, bradycardia, irregular pulse, T-wave changes, bundle branch block Rare: atrial fibrillation AV block first degree, STelevation, increase QRS Ziprasidone Frequent: tachycardia 2% (Geodon) Infrequent: 1QTc risk of torsades de pointes, (warning of sudden death with other drugs or conditions that prolong QTc intervals) bradycardia, atrial fibrillation Rare: first degree AV block, bundle branch block, ST-segment changes, T-wave change reported

Rare: Angina pectoris, CHF

Frequent: orthostatic hypotension ⬎5% (dose dependent) Infrequent: hypertension

Infrequent: MI Rare: Angina pectoris, myocarditis

Frequent: orthostatic hypotension ⬎5% hypertension 2% Infrequent: cerebrovascular accident, hemorrhage, migraine Rare: arteritis, pulmonary embolus Frequent: hypotension 7%, hypertension 0/⫹, syncope 1% Infrequent: vasodilation migraine, cerebral ischemia cerebrovascular accident deep vein thrombophlebitis Frequent: hypotension 1%, hypertension 1% Rare: thrombophlebitis, deep vein thrombophlebitis, pulmonary embolus, cerebral infarct, cerebrovascular accident

Infrequent: CHF, cardiac arrest Rare: angina pectoris, myocarditis

Infrequent: angina Rare: cardiomegaly, myocarditis

Frequent, 1/100 patients; infrequent, 1/100 to 1/1000; rare, ⬎1/1000; MI, myocardial infarction; CHF, congestive heart failure. 194

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TABLE 3. Important drug interactions with the antipsychotic medications Cardiovascular agents ACE Inhibitors Amiodarone

␣-Agonists (norepinephrine) Antiarrhythmic (Ibutilide fumarate) Anticoagulants Antihypertensives ␣-Methyldopa

Antihypertensive ␤-Blockers: propranolol

Antihypertensive Clonidine hydrochloride Antihypertensive Diuretics and smooth muscle relaxants

Class of antipsychotic

Potential interactions

Phenothiazines (Chlorpromazine) Phenothiazines, pimozide atypicals Phenothiazines, atypicals, clozapine Phenothiazines, atypicals

Prolong QTc/sudden death

Phenothiazines, clozapine

Decrease prothrombin

Phenothiazines, atypicals, clozapine

Hypotension; ? neurologic brain condition with haloperidol Augment hypotension

Phenothiazines (chlorpromazine & thioridazine), atypicals, clozapine Phenothiazines (fluphenazine), atypicals, clozapine Phenothiazines, atypicals clozapine

Hypotension (postural) orthostasis Prolong QTc unknown chance of sudden death Antagonize pressor effect

Variable hypotension Delirium May potentiate hypotension Prolong QTc/sudden death

Antihypertensive Guanethidine monosulfate

Phenothiazines, atypicals, clozapine

Antagonize antihypertensive effect Hypotension

Digitalis

Phenothiazines, atypicals clozapine Phenothiazines

Nitrates Quinidine

Phenothiazines Phenothiazines

Inotrope ␤-Agonist (isoproterenol)

Thioridazine may nullify inotropic effect May potentiate hypotension May potentiate cardiac effect

ACE, Angiotensin-converting enzyme.

Neuroleptics/Older Antipsychotics These agents are classified according to their chemical structures and are 70% effective in treating positive symptoms of schizophrenia, but are not very efficacious in treating other symptoms of psychosis. As a group these conventional agents are generally dopamine D2-blocking agents. D2 blockade is responsible for producing EPS, TD, and prolactin elevation. As a group, their anticholinergic side effects are related to the blockade of muscarinic M1 receptors; sedation and weight gain are related to blockade of H1 histaminic receptors, and orthostatic blood pressure effects are caused by ␣-1 adrenergic blockade. Curr Probl Cardiol, May 2002

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FIG 1. ECG of patient with previously normal tracing who had QT interval prolongation develop with therapeutic doses of thioridazine. The ECG change resolved 72 hours after treatment was stopped.

A useful approach for classification of neuroleptics is to separate the drugs into low- and high-potency subgroups. The low-potency agents require higher doses to achieve an antipsychotic effect and are generally more anticholinergic, sedative, and cause orthostatic hypotension. They have less EPS than high-potency neuroleptics and a risk of TD that increases with dose and length of use. ECG changes are also observed more frequently with these drugs. The high-potency drugs are more commonly used because they are the most cardio safe of all antipsychotics.14 They generally cause less sedation, weight gain, and hypotension but are more likely to cause EPS. Phenothiazines. Phenothiazines are the oldest class of modern psychoactive medications. Their spectrum of cardiovascular effects is reviewed in Table 1. Chlorpromazine, the prototypic drug of this class, is an aliphatic low-potency phenothiazine available since 1952. It has been the most extensively studied of all antipsychotics. It has been shown to cause ECG changes, which include prolongation of QTc/QT interval, blunting and notching of T waves, and U wave formation. It is associated with a low incidence of cardiac disorders that include cardiomegaly; venous thromboembolic disease; congestive heart failure (CHF); refractory ventricular arrhythmias; mucopolysaccharide accumulation in coronary arterioles; and electrophysiologic abnormalities, including prolongation of atrial and ventricular conduction, and refractory times.15,16 Thorazine has direct vasodilator activity, ␣-adrenergic blocking activity, and is frequently associated with hypotension, which is reversible over a short period. If treatment of hypotension is necessary, a pure ␣-agonist agent should be used because epinephrine can cause paradoxical hypotension if used concurrently with phenothiazines.17 196

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TABLE 4. Medications that can prolong QTc intervals Antiarrhythmic medications: Class I A: disopyramide, N-acetyl procainamide, procainamide, quinidine, Class III: amiodarone, bepridil, bretylium tosylate, d-sotalol, dofetilide, sotalol hydrochloride, Antibiotics: erythromycin, gatifloxacin, moxifloxacin, pentamidine, sparfloxacin trimetoprim/ sulfamethoxazole Antimalarials: quinine, chloroquine, halofantrine hydrochloride Calcium channel blockers: bepridil, prenylamine, terodiline Antipsychotic medications: chlorpromazine, droperidol, haloperidol (in high doses and iv form), pimozide, thioridazine, ziprasidone Antidepressants: All TCAs especially amitriptyline hydrochloride, doxepin hydrochloride, maprotiline; citalopram hydrobromide, lithium Miscellaneous: amantadine, chloral hydrate, ketanserin, organophosphates (veterinary), probucol, succinylcholine chloride, tacrolimus, vasopressin

Thioridazine, a piperidine low-potency agent, has recently received a black-box warning because of its tendency to prolong the QTc interval (Fig 1), increasing the risk of torsades de pointes and sudden death.18 Thioridazine can also lead to other cardiac conduction abnormalities and ventricular arrhythmias. Mesoridazine causes similar but fewer cardiovascular effects as thioridazine, including tachycardia. Other low-potency agents appear to present similar but slightly less risk of QTc effects. Phenothiazines inhibit actions of guanethidine monosulfate and ␣-methyldopa in hypertensive patients. They also interact with angiotensinconverting enzyme inhibitors,13 clonidine hydrocloride, and nitroglycerin, resulting in synergistic hypotension and orthostasis. Phenothiazines (chlorpromazine and thioridazine) also interact with propranolol, each altering the metabolism of the other, thereby enhancing the effects of both drugs.13 Drugs of this class that may interact with other medications13,19-27 to prolong the QTc interval are listed in Table 4. Phenothiazines can also diminish the effects of warfarin and increase digoxin absorption from the gastrointestinal tract by their anticholinergic actions on gastrointestinal mobility. To avoid development of QTc/QT interval prolongation, low-potency phenothiazines should not be used in patients receiving class I and III antiarrhythmic agents (Tables 3 and 4), and should be avoided in patients with syndromes or histories that increase risks of QTc prolongation as described in Table 5. High-potency phenothiazines (trifluoperazine hydrocloride, fluphenazine, acetophenazine maleate, and perphenazine) are still used with outpatients prone to recurrent positive-symptom psychosis, and are also used to treat some severe personality disorders. They cause a much lower Curr Probl Cardiol, May 2002

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TABLE 5. Conditions that increase the risk of QTc prolongation Childhood history of recurrent seizures or syncopal attacks History of dizziness, lightheadedness, palpitations Idiopathic long QT syndrome Abnormal electrolytes, especially low potassium or magnesium History of underlying cardiac disease such as atrioventricular block, ischemic heart disease, or congestive heart failure Elderly and female patients Substance abusing patients especially those using alcohol and cocaine Patients taking of multiple medications each of which prolongs QTc intervals (eg an antipsychotic, antidepressant, and antibiotic) Drug interactions which increase the dose of a medication with QTc effects

incidence of cardiac side effects, such as ECG abnormalities and hypotension, than low-potency phenothiazines. Fluphenazine is available as a long-acting depot formulation, which is administered every 2 to 4 weeks. Adverse effects, which develop when using long-acting depot, are extremely difficult to eliminate. Butyrophenones. This group is chemically distinct from phenothiazines. Haloperidol is the only representative from this group with a clinical indication for treatment of psychosis, and is probably the most widely prescribed antipsychotic medication, though this appears to be changing. Droperidol, an anesthetic adjuvant, is also a member of this class. It is sometimes used to gain behavioral control of severely agitated and psychotic patients. Haloperidol is used in emergency, inpatient, and outpatient settings. It is available orally, parenterally, and as a long-term depot intramuscular suspension. Oral and intramuscular injections of haloperidol are among the most cardio safe of all antipsychotics. Haloperidol has few cardiovascular side effects and is least likely to produce prolongation of QTc intervals18 compared with phenothiazines and atypicals. Because of this, many clinicians consider it the agent of choice in the elderly and in patients with cardiac disease. Haloperidol also causes a very low incidence of hypotension and other ECG abnormalities (Table 1). However, intravenous haloperidol and droperidol both can significantly prolong QTc interval, increasing the risk of torsades de pointes14,28 and the possibility of sudden death. Thioxanthenes. This group of neuroleptics is a distinct class of drugs different from phenothiazines. One agent, thiothixene, has a reputed low incidence of hypotension and nonspecific ECG changes.29 However, another agent in this class, chlorprothixene, causes more hypotension and ECG abnormalities with rare reports of sudden death being described.29 198

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Indolones. This distinct class of drugs has a prototype medication called molindone hydrochloride. Side effects from molindone hydrochloride are quite benign, including weight loss, rare hypotension, and nonspecific ECG abnormalities.29 Although molindone hydrochloride is relatively cardio safe, many practitioners find it to be a poor antipsychotic. Dibenzoxazepines. Loxapine is associated with rare reports of ECG abnormalities, tachycardia, hypotension, and hypertension.29 Diphenylbutylpiperidine. The diphenylbutylpiperidine, pimozide, is a pure dopamine antagonist that is approved for use in Tourette’s disorder. It has also been used to treat monosymptomatic hypochondriasis and delusional disorders. It is associated with arrhythmias and fatal reactions at doses higher than those recommended. Cardiovascular side effects include tachycardia, hypotension, hypertension, and ECG changes that include QTc/QT interval prolongation and T wave abnormalities.29-31

Atypical or Novel Antipsychotics Clozapine. Clozapine, a dibenzoxazepine, was discovered accidentally in the 1970s when scientists were trying to synthesize a new antidepressant related to imipramine. This discovery represented a major pharmacotherapeutic advance. Clozapine has been shown to produce a significant remission in 30% of patients found refractory to other neuroleptics, has little EPS, and minimal risk of TD. Clozapine has special status as the only medication proven effective for treatment of neuroleptic refractory schizophrenia.12 Like other atypical medications, it is also useful in treating negative symptoms of schizophrenia.32-35 Unlike neuroleptics, clozapine blocks multiple 5HT2 receptors36-40 (serotonin receptors 5HT2A, 5HT1A, 5HT2C, 5HT3, 5HT6, and 5HT7) more effectively than D2 receptors. It acts somewhat on the D2 receptor, but also on D1, D3, and D4.36-40 In addition, it has effects on muscarinic, histaminic, and ␣-1 and ␣-2 adrenergic receptors.40,41 In addition, because of the risk of agranulocytosis, clozapin has generally been used as a second-line drug for neuroleptic refractory schizophrenia.12,30,42 In February 2002, the FDA and Novartis (manufacturer) strengthened the boxed warning to include an increased risk of fatal myocarditis. However, the revised current estimate of the risk of developing agranulocytosis with complete blood count monitoring is 0.4%.12 This risk is reduced further after 6 months. Moreover, the ability to treat agranulocytosis by use of granulocyte colony stimulating factor, reverse isolation, and prophylactic antibiotic treatment12 should, in the near future, permit even greater use of this effective medication for treatment of schizophrenia. Curr Probl Cardiol, May 2002

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Clozapine causes significant weight gain and therefore should be used with caution in diabetics and patients with abnormal lipid profiles. Clozapine-induced weight gain can occur in normal weight patients, and this drug-induced weight gain can introduce obesity as a new cardiovascular risk factor for some patients. The effects of clozapine on the cardiovascular system are varied. Approximately 25% of patients receiving all forms of antipsychotics will have ECG changes.19,43,44 The prevalence rate of new ECG abnormalities in patients in whom clozapine is started, with a normal baseline ECG, was 24.5%.19 Sinus tachycardia is reported in up to 25% of patients.29 ECG changes include QTc prolongation, which increases in a dose-dependent fashion, ST-T elevation that can mimic ischemic heart disease,44 QT interval changes, ventricular tachycardia, atrial and ventricular extrasystoles, T-wave inversion, ST-segment depression, and atrioventricular blocks. Vascular effects include hypotension in 9% of patients, whereas hypertension is seen in 4% of cases.29 Fludrocortisone acetate has been added to clozapine to minimize this drug-induced hypotension.20 Infrequent deep vein thrombosis and pulmonary embolism and rare cerebral transient ischemic attacks have been described.29 Direct cardiac effects include a 1% risk of angina. The drug has rarely caused cardiac arrest in healthy volunteers receiving the drug.21 These rare direct cardiac effects are reviewed in Table 2. Risperidone. Risperidone was introduced in 1994 as the first novel antipsychotic drug of the benzisoxazole class. It has no associated risk of agranulocytosis. Like other novel antipsychotics, it is effective for both positive and negative symptoms of schizophrenia and may be especially helpful for patients who have prominent cognitive symptoms associated with schizophrenia. It acts on 5HT2A, 5HT7, and D2 receptors40and is better tolerated than clozapine.12,30,42 At lower starting doses (1 mg twice daily up to 6 mg/d), it is generally free of EPS and TD. At higher doses, EPS may appear, and this medication takes on the side-effect profile of older neuroleptics. Appearance of EPS suggests that the clinician should lower the dose rather that use antiparkinsonian medications.12,30,42 Sinus tachycardia is reported in up to 5% of patients.29-31,42 ECG findings of prolonged QTc are slight. Other ECG findings include changes in QT interval, ventricular tachycardia, palpitations, premature atrial and ventricular beats, T-wave inversion, ST-segment depressions, and atrioventricular blocks. Vascular complications include a 5% incidence of hypotension29 and a low incidence of hypertension. There are infrequent reports of renal 200

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impairment and complication of MI. There are also reports of myocarditis and angina pectoris. One reported case of a severe overdose was associated with hyponatremia, hypokalemia, and ECG widening of both QRS and QT intervals.45 Olanzapine. Olanzapine was introduced in 1996 as a second novel antipsychotic drug. It belongs to the thienobenzodiazapine class of medications, which are chemically most similar to clozapine. However, unlike clozapine, it does not produce agranulocytosis. It is effective for both positive and negative symptoms of schizophrenia and has an additional indication for patients with manic symptoms. Similar to clozapine, it has broader receptor affinities than risperidone, acting on 5HT2A, 5HT2C, 5HT3, 5HT6, and D2, D1, D3, and D4 receptors, acetylcholine, and histamine.40 It has minimal EPS and a rare incidence of TD, with moderate and probably transient effects on prolactin levels.12 Olanzapine is started in the patient (10 mg/d) at bedtime because of sedation, and often is increased (20 mg/d). Because of significant weight gain, olanzapine should be used with caution in diabetics, patients with abnormal lipid profiles, or in patients where weight gain may add additional cardiac risk. Sinus tachycardia is reported in up to 3% of patients.29 A Pfizer study (054) designed with the Food and Drug Administration (FDA)18 to measure QTc prolongation indicated that olanzapine was among the least likely of antipsychotics to cause prolonged QTc interval. Other infrequent ECG findings include ventricular tachycardia, premature atrial and ventricular beats, T-wave inversion, ST-segment depressions, and atrioventricular blocks.29,31 Also reported infrequently are CHF and cardiac arrest.29,31 Quetiapine. Quetiapine was introduced in 1997 and is a dibenzothiazepine derivative. It is effective for both positive and negative symptoms of schizophrenia and has no significant EPS, risk of TD, or prolactin effects. It has a unique pharmacologic receptor profile with high affinities for 5HT2A, 5HT6, 5HT7, and D2 receptors.40 Its side-effect profile is related to its ␣-1 and ␣-2 activity, causing orthostatic hypotension. Its histamine receptor effects cause sedation and weight gain.40 Quetiapine is started in the patient (25 mg twice daily) and titrated upward (300 mg/d with the upper dose range of 750 mg/d).12,30 Sinus tachycardia is reported in up to 7% of patients and palpitations are common.29 The FDA/Pfizer study (054)18 indicated that quetiapine is generally safe, with a low frequency of QTc prolongation but a slightly greater effect on QTc than risperidone or olanzapine. Other infrequent ECG findings include bradycardia, T-wave changes, and Curr Probl Cardiol, May 2002

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bundle branch block. Rare ECG effects include atrial fibrillation, first-degree atrioventricular blocks, ST-T elevations, and increased QRS duration.29 Quetiapine causes hypotension in approximately 7% of patients29 and infrequent hypertension. Direct cardiac effects are unusual (Table 1). Ziprasidone. Ziprasidone, with a novel chemical structure, had a delayed introduction to the market until February 2001. Ziprasidone did not become available until a QTc safety study was jointly completed by Pfizer and the FDA.18 Ziprasidone is effective for treatment of both positive and negative symptoms of schizophrenia, and may also improve cognitive functioning in schizophrenia and dementia.46 It has little significant EPS, risk of TD, or prolactin effects. It has a unique pharmacologic receptor profile with high affinities for 5HT2A, 5HT1A, 5HT1D, 5HT2C, 5HT7, D2, and D3.40 It is also the only novel antipsychotic that is a serotonin 1D antagonist, a serotonin 1A agonist, and also inhibits both serotonin and norepinephrine reuptake.40 Ziprasidone is probably the least sedating of atypical medications and causes little or no weight gain. Its most common side effects are nausea (in about 20% of outpatients), insomnia (in about 50% of outpatients), and it may show an “awakening reaction” where a persistently ill patient suddenly shows a dramatic improvement.22 Ziprasidone is started in the patient (20 mg twice daily) with food and can be titrated upwards to a maximum (80 mg twice daily).30,31 Sinus tachycardia is reported in up to 2% of patients.29 The FDA/Pfizer study (054)18 led to a warning of drug interactions that can lead to QTc/QT prolongation34 with an increased risk for occurrence of torsades de pointes leading to sudden death. The mean QTc increase from baseline with ziprasidone was significant and greater than risperidone, olanzapine, quetiapine, and haloperidol, but was less than the prolongation observed with thioridazine. There is a warning18 that ziprasidone not be used in conjunction with any other medications (Table 3) or medical conditions that prolong QTc/QT interval (Table 5). Ziprasidone also causes hypotension/hypertension in approximately 1% of patients. Other infrequent and rare ECG findings and direct cardiac effects are reviewed in Table 2.

QTc and Antipsychotics One area of recent interest, concern, and controversy is the clinical effect and meaning of changes in the QTc interval. These cardiac safety issues came to the forefront when sertindole,23 another novel antipsychotic, was pulled from the market because of QTc prolongation and risk 202

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of sudden death. Subsequently, thioridazine received a black-box warning18,31 because of its dangerous potential for prolonging QTc interval. Ziprasidone had its FDA approval delayed because of concerns about its effects on QTc interval.18,22 Most cardiologists believe that a QTc reading of more than 500 ms22-28,30 puts a patient at significant risk for torsades de pointes, ventricular fibrillation, and sudden death. Currently, all novel antipsychotics, when used alone, cause QTc readings of less than 500 ms, including ziprasidone. Therefore, in the average healthy young patient without comorbid medical conditions, and in the absence of polypharmacy, there is little danger from prolongation of QTc interval from use of atypical antipsychotics agents. However, patients who have other risk factors for QTc prolongation and sudden death22,24-29,31,43 (Table 5) can be deleteriously affected by these drugs. Those drugs that are used in combination and can also cause serious QTc prolongation19,22-27,29,31,40 are listed in Table 4.

Antidepressants Depression is the most common psychiatric illness and is frequently present in patients with cardiovascular disease. Recently, depression has been shown to be associated with an increased cardiovascular mortality in patients with or without cardiac disease3-7,47,48 In 1 study, the diagnosis of depression increased the risk of MI more than 4-fold after controlling for both medical risk factors and other psychiatric diagnosis.6 There is mounting evidence that depression itself may be an independent risk factor for cardiovascular disease3-7,10,47 and a predictor of death in survivors of acute MI.3 It has not yet been determined whether treating depression removes it as a risk factor for cardiovascular disease. In a recent study of 653 cases of smokers who had an MI, 143 patients were on fluoxetine, fluoxamine, paroxetine hydrochloride, or sertraline hydrochloride. This study demonstrated a significant association between SSRI use and lower odds of having an MI among smokers.10 More extensive clinical trials using SSRIs to reduce morbidity and mortality in patients with coronary artery disease are in progress. Antidepressant medications (Tables 6 through 10) have had a major impact on depression, relieving symptoms in 70% of treated participants in clinical trials compared with 30% who received placebo.49,50 The theoretical basis of antidepressant therapy was originally thought to be related to the fact that depressive symptoms were caused by a relative deficiency in the brain of the neurotransmitters norepinephrine, serotonin, or dopamine.51 These medications were thought to act by blocking Curr Probl Cardiol, May 2002

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TABLE 6. Selective serotonin reuptake inhibitors and newer antidepressants Reuptake blockade

Postsynaptic blockade

Reuptake blockade

Receptors

NA

DA

5HTs

Side effects caused by receptor blockade

Sweating anxiety

EPS Prolactin level

Diarrhea Nausea

⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹⫹ ⫹⫹⫹⫹ ⫹⫹⫹⫹

⫹

0? ⫹ 0 0 ⫹⫹⫹ Presynaptic ⫹/⫺

⫹/⫺ ⫹ 0?

⫹/⫺ 0 0?

0 ⫹⫹ 0?

⫹/⫺

⫹

⫹

Selective serotonin reuptake inhibitors (SSRIs) Citalopram hydrobromide 0? Fluoxetine ⫹ Fluvoxamine ⫹ Paroxetine hydrochloride ⫹/⫺ Sertraline hydrochloride ⫹ Venlafaxine hydrochloride Other newer antidepressants Bupropion hydrochloride Nefazodone hydrochloride Mirtazapine

Trazodone hydrochloride

⫹⫹/⫹⫹⫹

⫹⫹⫹⫹, Greatest side effect; ⫹/⫺, minimal side effect; 0, nil; NA, noradrenaline; DA, dopamine; 5HTs, serotonin; ACH, cholinergic (muscarinic); H1, histamine

TABLE 7. Tricyclic antidepressants and less commonly used heterocyclic antidepressants Reuptake blockade

Postsynaptic blockade

Reuptake blockade

Receptor

NA

DA

5HTs

Side effect caused by receptor blockade

Sweating anxiety

EPS Prolactin level

Diarrhea nausea

⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹⫹ ⫹

⫹ ⫹⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹⫹

⫹⫹ ⫹/⫺ ⫹⫹⫹ ⫹/⫺ ⫹ ⫹⫹ 0 ⫹/⫺ ⫹/⫺ ⫹/⫺

Amitriptyline Amoxapine Clomipramine Desipramine hydrochloride Doxepin hydrochloride Imipramine Maprotiline Nortriptyline hydrochloride Protriptyline hydrochloride Trimipramine

⫹⫹⫹⫹, Greatest side effect; ⫹/⫺, minimal side effect; 0, nil; NA, noradrenaline; DA, dopamine; 5HTs, serotonin; ACH, acetylcholine (muscarinic); H1, histamine 204

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TABLE 6. Continued Postsynaptic blockade

Postsynaptic blockade

Postsynaptic blockade

ACH

(H1)

(␣ 1)

Blurred vision Dry mouth Memory loss

Sedation Weight gain Hypotension Histamine

Postural Hypotension Dizziness Tachycardia

0? ⫹/⫺ 0 ⫹⫹ ⫹/⫺

0? ⫹/⫺ 0 0 0

0 0 ⫹ 0

0 ⫹/⫺ ⫹/⫺ ⫹⫹⫹⫹ sedation not an H1 effect H1 ⫽ ⫹/⫺ ⫹

0

Usual dose mg/d

Max dose mg/d

0? ⫹/⫺ ⫹/⫺ ⫹/⫺ ⫹

20–40 20–40 100–300 20–40 50–150

10–60 10–80 50–400 10–50 25–200

0 ⫹/⫺ ⫹⫹ ⫹/⫺?

75–225 225–450 300–600 15

25–350 100–450 100–600 15–45

⫹⫹⫹⫹

200–600

50–600

Usual dose mg/d

Dose range mg/d

100–300 200–400 125–300 150–300 150–300 150–300 150–225 75–150 30–60 150–300

25–450 50–600 25–500 25–400 25–350 25–450 25–225 20–200 10–80 25–350

TABLE 7. Continued Postsynaptic blockade

Postsynaptic blockade

ACH

H1

␣1

Blurred vision Dry mouth Memory loss ⫹⫹⫹⫹ ⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹ ⫹⫹ ⫹⫹⫹⫹ ⫹⫹⫹

Sedation Weight gain Hypotension ⫹⫹⫹ ⫹⫹ ⫹⫹⫹ ⫹ ⫹⫹⫹⫹ 0 ⫹⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹⫹⫹

Postural hypotension Dizziness Tachycardia ⫹⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹⫹ ⫹⫹ ⫹⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹⫹⫹

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Postsynaptic blockade

205

TABLE 8. Cardiac toxicity of the antidepressant medications Selective serotonin reuptake inhibitors Sinus tachycardia/bradycardia, atrial fibrillation bundle branch block, 1QTc in overdose. The value of ECG in predicting cardiac toxicity is unknown Bupropion hydrochloride Sinus tachycardia, bradycardia atrioventricular block Extrasystoles, cardiac arrest Trazodone hydrochloride and Nefazodone hydrochloride Sinus bradycardia/tachycardia, ventricular extrasystoles AV block, ventricular ectopy, ventricular systoles Venlafaxine hydrochloride Sinus tachycardia and bradycardia, QTc prolongation first degree AV block, bigeminy, bundle branch block Mirtazapine Sinus tachycardia/bradycardia, ventricular extrasystoles, bigeminy Tricyclic antidepressants Sinus/ventricular tachycardia, supraventricular tachyarrhythmias, atrial fibrillation, heart block, 1PR, 1QRS and 1QT intervals, ST-T wave segment changes

reuptake of these neurotransmitters in the brain, thus potentiating their action. More recently the “receptor sensitivity hypothesis”52 implies that depression is caused by abnormal regulation of monoamine receptor sensitivity. The “dysregulation hypothesis”53 suggests that depression is caused by a dysregulation of homeostatic mechanisms controlling neurotransmitter receptor functioning. Taking center stage as the neurobiologic explanation for depression is the monoamine hypothesis of gene transcription. This hypothesis suggests that there is no clear evidence of monamine deficiency or deficits in monoamine receptors. Instead it focuses on the fact that there is a pseudomonoamine deficiency because of deficiency in signal transduction from the monoamine neurotransmitter to its postsynaptic neuron. The presumed deficit is in the second messenger system, which led to the formation of intracellular transcription factors that control gene expression.40 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.40 As a group, all these hypotheses propose that antidepressants work by reversing an actual or functional monoamine deficit state.

Tricyclic Antidepressants (TCAs) TCAs have had wide use for over 4 decades. Similar to SSRIs, they are used for depression, bipolar disorders in the depressive phase, dysthymic disorders, postpartum depression, postpsychotic depression of schizo206

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FIG 2. Electrocardiogram of patient who had intraventricular conduction defect and prolongation of the QTc interval develop with overdose of amitriptyline hydrochloride. The ECG became normal 48 hours later.

phrenia, schizoaffective disorders, panic disorders, social phobia, posttraumatic stress disorder, eating disorders, obsessive-compulsive disorders, and chronic pain syndromes.49 Like SSRIs and monoamine oxidase inhibitors (MAOIs), TCAs work by reversing a functional monoamine deficit state. Side effects produced by TCAs are caused predominately by noradrenergic, dopaminergic, and serotoninergic actions, and by effects at cholinergic/muscarinic, ␣1adrenergic, and histamine receptors (Table 7). Receptor effects are rapid and typically produce side effects first, followed by delayed antidepressant efficacy, which occurs from 3 to 12 weeks after initiation of pharmacotherapy. TCAs were initially synthesized as antihistamines and are divided into the tertiary amine subclass (imipramine, amitriptyline hydrochloride, trimipramine, and doxepin hydrochloride); the secondary amine subclass (desipramine hydrochloride, nortriptyline hydrochloride, and protriptyline hydrochloride); and the heterocyclic subclass (amoxapine and maprotiline).51,54-56 Tertiary amines and heterocyclics cause the highest incidence of anticholinergic side effects, orthostatic hypotension, and sedation. All these agents are known to cause cardiac toxicity that can limit their use (Table 8). The toxicity of these drugs is because of both a quinidine-like effect and anticholinergic activity,57 which can slow intracardiac conduction, prolong QTc interval, or both (Fig 2). These drugs can also decrease ECG R-R interval, indicating an effect on autonomic input to the heart.58 Patients at risk for cardiac side effects from these drugs include those with significant cardiovascular disease, Curr Probl Cardiol, May 2002

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TABLE 9. Cardiovascular drug-drug interactions with the newer SSRI antidepressants Drug

Interaction

Citalopram hydrobromide

Weak inhibitory effect on CYP2D6, 1A2, and C19. 1 levels of metoprolol: ⫾ with warfarin, when combined can increase the INR. Erythromycin can 1 citalopram hydrobromide concentration by inhibiting CYP 3A4. May displace highly protein bound drugs 1 blood levels of warfarin, digitoxin; may inhibit cytochrome P4502D6 and P4502C9 activity 1 plasma concentrations of type Ic antiarrhythmics (flecainide acetate, propafenone hydrochloride). Can cause hyponatremia, worse if combined with a loop diuretic (bumetanide, furosemide, torsemide). Can inhibit the metabolism of metoprolol/propranolol resulting in bradycardia, hypotension/heart failure. Use of ␤-blockers (sotalol, atenolol) is preferred. Can inhibit metabolism of HMG-Co reductase inhibitors (lovastatin/simvastatin) resulting in myositis/rhabdomyolysis. 1 warfarin raising plasma concentration/prothrombin time; can reduce clearance of theophylline, 1 plasma level; can 1 plasma concentration of propranolol. May inhibit activity of P450IIIA4, P450IA2, P4502C9 and P45034A. Anecdotal reports of 1 digoxin levels when used with warfarin. Diltiazem coadministration can cause bradycardia. Inhibitor of P4502D6, 1 plasma concentrations of encainide hydrochloride, flecainide acetate, propafenone hydrochloride; possible interaction with warfarin, potentiating warfarin’s effects without altering the PT; highly protein bound and can displace digoxin, propranolol, but no adverse effects seen. Can cause hyponatremia worsened with the use of loop diuretics. May displace highly protein bound drugs (warfarin, digitoxin), 1 free blood levels; may inhibit cytochrome P4502D6 (less than other SSRIs) 1 plasma concentrations of type Ic antiarrhythmics (flecainide acetate, propafenone hydrochloride).

Fluoxetine

Fluvoxamine

Paroxetine hydrochloride

Sertraline hydrochloride

Adapted from Nurenberg JR, Frishman WH. Cardiovascular considerations with use of psychoactive medications. In: Frishman WH, Sonnenblick EH, editors. Cardiovascular pharmacotherapeutics. New York: McGraw Hill; 1997 p. 1046.

underlying conduction system disease, conditions that prolong QTc interval (Table 5), or those on multiple medications that affect QTc interval (Table 4). A routine ECG before treatment with TCAs is generally recommended for patients over 40 years old, patients with risk factors for heart disease, or patients who are on multiple medications that affect cardiac parameters. Except in overdose and with some polypharmacy, major cardiac complications from TCAs are rare in individuals with no underlying cardiac pathology. TCAs can be given to patients with first-degree heart block and isolated 208

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TABLE 10. Cardiovascular drug-drug interactions with newer antidepressants Drug Mirtazapine

Nefazodone hydrochloride

Trazodone hydrochloride

Venlafaxine hydrochloride

Interaction Mirtazapine itself is a substrate of CYP2D6, 1A2, 3A4. No potent inhibitory effect on these enzymes. Use of mirtazapine with central ␣ 2 agonists may increase the risk of central nervous system depression. Highly protein bound, may cause 1 free concentrations of other drugs. Can 1 cilostazol (antiplatelet agent) levels. When added to digoxin, digoxin levels can 1 15–30%, monitored closely. Interact with HMG-Co A reductase inhibitors (lovastatin/simvastatin) as these are CYP3A4 substrates: rhabdomyolysis reported. Use pravastatin sodium/fluvastatin as they undergo little/no metabolism by CYP3A4. Nefazodone hydrochloride 1 calcium channel blockers, hypotension should be monitored. Coadministration of nefazodone with dofetilide can 1 the QT interval. Caution 1 risk of QT prolongation/ventricular arrhythmia with amiodarone and others medications (see Table 4). It can decrease the clotting times when used with warfarin; monitor clotting times or trazodone should be stopped. Weak inhibitor of P4502D6 (clinical significance unknown). Can raise diastolic blood pressure 15 mm Hg (dose dependent effect) interfering with effects of antihypertensive medications.

left- or right-bundle branch blocks, unless associated with previous syncope. However, TCAs should be avoided in patients with prolonged QTc/QT interval and in patients with Wolff-Parkinson-White Syndrome who have atrial fibrillation/flutter.59 An acute MI is an absolute contraindication to treatment with these drugs. TCAs should be discontinued before operation because of the possibility of perioperative hypertensive and hypotensive episodes.55,59 Severe cardiac toxicity with and without overdose includes hypotension, a variety of supraventricular and ventricular arrhythmias, and heart block. Severe hypotension requires the administration of fluids and pressors to counteract the anti-␣-adrenergic effects of these drugs. In patients with significant arrhythmia, a QRS duration of more than 10 ms, or a serum tricyclic level more than 1000 ng/mL, careful cardiac monitoring is required, preferably in an intensive care unit. When treating ventricular arrhythmias, one must avoid therapy with procainamide hydrochloride, quinidine, and disopyramide, which can precipitate heart block. For heart block, a temporary pacemaker may be used. Orthostatic hypotension is a common adverse reaction with TCAs, Curr Probl Cardiol, May 2002

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TABLE 11. Drug-drug interactions involving tricyclic antidepressants Exacerbates hypotension ␣-methyldopa ␤-Adrenergic blockers ␣-Adrenergic blockers Clonidine hydrochloride Diuretics Nitrates Angiotensin converting enzyme inhibitors Angiotensin II receptor blockers Calcium-channel blockers Exacerbates hypertension Sympathomimetics (TCAs may decrease pressor response of dopamine) Cardiotoxicity increased Type I and III antiarrhythmic drugs Thioridazine Mesoridazine (Review Table 4) Other effects Tricyclics may increase the effects of warfarin Tricyclics may block the effects of guanethidine monosulfate Adapted from Nurenberg JR, Frishman WH. Cardiovascular considerations with use of psychoactive medications. In: Frishman WH, Sonnenblick EH, editors. Cardiovascular pharmacotherapeutics. New York: McGraw Hill; 1997 p. 1045.

particularly in elderly patients treated with a low salt diet or with antihypertensive drugs that include ␣-methyldopa, ␣-adrenergic blockers, clonidine hydrocloride, and diuretics.1 TCAs can potentiate the effects of warfarin sodium and may block the antihypertensive effects of guanethidine monosulfate. There is a potential for added cardiotoxicity when TCAs are combined with phenothiazines such as thioridazine, mesoridazine, and others13 as described in Tables 8 and 11.

Monoamine Oxidase Inhibitors These drugs are the oldest of the antidepressants. The main problem in clinical use is dangerous interactions in medicated patients who receive concurrent adrenergic substances, such as cold remedies, tyramine-rich foods, meperidine hydrochloride, antidepressants of another class, or even another MAOI (Table 12). As new MAOIs are developed that do not require dietary restrictions or have fewer drug interactions, use of these effective agents may increase again. MAOIs are used by physicians to treat typical and atypical depression and anxiety disorders such as panic disorder with agoraphobia, social phobia, and posttraumatic stress disorder.1,61 The presumed mechanism by which these drugs provide benefit in 210

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TABLE 12. Drugs to be avoided during monoamine oxidase inhibitor treatment Never use Antihypertensives (methyldopa, guanethidine, monosulfate reserpine, pargyline hydrochloride) Sympathomimetics (amphetamine, cocaine, dopamine, ephedrine, epinephrine, isoproterenol, L-dopa, metaraminol, methylphenidate, norepinephrine, oxymetazoline, phenylephrine, phenylpropanolamine pseudoephedrine,) Serotonin-reuptake inhibitors (clomipramine hydrochloride, tryptophan, venlafaxine hydrochloride) Bupropion hydrochloride Narcotics (meperdine, codeine, and others) Dextromethorphan Use cautiously Angiotensin converting enzyme inhibitors Angiotensin II receptor blockers Hydralazine Oral hypoglycemics Propranolol Tricyclic and tetracyclic antidepressant drugs Calcium channel blockers Digoxin Adapted from Nurenberg JR, Frishman WH. Cardiovascular considerations with use of psychoactive medications. In: Frishman WH, Sonnenblick EH, editors. Cardiovascular pharmacotherapeutics. New York: McGraw Hill; 1997 p. 1044.

depression is by inhibition of the metabolism of both sympathomimetic amines and serotonin. They can also influence neuronal reuptake of norepinephrine, dopamine, and serotonin through a complicated series of enzymatic interactions. Two subtypes of MAOIs have been described (MAO-A and MAO-B). MAO-A is located in the gut, central nervous system, sympathetic terminals, and skin. When irreversibly inhibited, MAO-A permits unmetabolized tyramine to be absorbed, resulting in a hypertensive crisis.61 MAO-B enzyme is located in the central nervous system, liver, and platelets. Classic MAOIs are irreversible in their effects and nonselective for MAO, and include phenelzine sulfate (Nardil), tranylcypromine sulfate (Parnate) and isocarboxazid (Marplan). Reversible selective inhibitors of MAO-A (including clorgyline, moclobemide, brofaramine, befloxatone, cimoxatone, and toloxatone) are under study and show promise, as they do not create hypertensive interactions with tyramine-rich foods and other medications. New efforts have also been made to develop a selective inhibitor of MAO-B enzyme. Seligiline, a selective inhibitor of MAO-B, in a new transdermal form,62 does not appear to produce hypertensive interactions. Therefore, the usual dietary restrictions with MAOIs may Curr Probl Cardiol, May 2002

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not be required when using this new form. Currently, no selective MAO-A or MAO-B inhibitor is FDA approved for treatment of depression. The effect of MAOIs on neurotransmitters are seen in a few days; however, a clinical effect on depression takes at least 2 to 6 weeks. Because older nonselective MAOIs are incompatible with other antidepressants or each other, a period of 2 weeks must pass before a different antidepressant drug can be substituted. This situation may change when selective inhibitors of MAO-A and MAO-B subtypes become readily available. The most dreaded cardiovascular complication of MAOI therapy is precipitation of an adrenergic crisis because of concurrent ingestion of sympathomimetic drugs or pressor amines such as tyramine, which is also found in some foods and beverages. These reactions can be quite serious and include stroke or death from severe hypertension. Drugs that dangerously interact with MAOIs are listed in Table 12. Treatment of hypertensive crises consists of inducing hypotension by blockade of ␣-adrenergic receptors with parenteral phentolamine or by use of nitroprusside, chlorpromazine, or both for their direct vasodilator effects. In patients in whom a hypertensive crisis develops, hypotensive blockade is often necessary for at least a week, because MAOI blockade is only slowly reversible. Premature cessation of hypotensive treatment, before reversal of MAOI by the body homeostasis, can cause symptoms of hypertensive crisis to re-emerge. ␣-Adrenergic agonists should be avoided because their predominant clinical effect in patients receiving MAOIs may intensify vasoconstriction and thus worsen hypertension. MAOIs do not affect peripheral effects of epinephrine and norepinephrine because they are metabolized by catechol O-methyltransferase.15,17 Acute increases in blood pressure have also been described with concomitant risperidone, meperidine hydrochloride, and guanethidine monosulfate therapy. Hypertensive crisis has been described rarely in patients on initial exposure to an MAOI in the absence of a tyramine meal. In this case, another MAOI can be given.32,63 Postural hypotension is a common complication of MAOI treatment. This effect is dose-related and may limit therapy.55,64 An incidence of 17% has been reported with tranylcypromine sulfate and 11% with phenelzine sulfate.1,32 This side effect can worsen if patients are receiving diuretics or other antihypertensives. Episodes of hypotension almost always respond to supine posture. In severe cases of hypotension, intravenous fluids may be required, and pressor amines should be avoided if possible. 212

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Selective Serotonin Reuptake Inhibitors SSRIs and their relative side effect profiles are reviewed in Table 6. These include fluoxetine (Prozac), paroxetine hydrochloride (Paxil), sertraline hydrochloride (Zoloft), fluvoxamine (Luvox), and the latest one, citalopram hydrobromide (Celexa). Compared with TCAs that block reuptake of serotonin and norepinephrine, SSRIs are pure serotonin reuptake blockers and have little effect on other neurotransmitters. These drugs have little or no anticholinergic, antihistaminic, or ␣-adrenergic effects, but do cause serotonin-related side effects (ie, sexual, anxiety, sweating, nausea, diarrhea, and constipation). SSRIs have virtually eclipsed other major antidepressants because of their relatively favorable cardiac side-effect profile and comparable clinical efficacy in milder forms of depression.65 There have been some conflicting reports that SSRIs are slightly less effective than TCAs for treatment of severe depression. On the other hand, SSRIs appear less likely than TCAs to unmask a manic phase in patients with bipolar disorder.66 Major side effects of SSRIs are caused by stimulation of certain known receptors, which include: nausea (5HT3 stimulation in hypothalamus and midbrain); diarrhea (5HT3 and 5HT4 receptors in the gut); and headache, agitation, and panic attacks (stimulation of 5HT2A and 5HT2C receptors). SSRIs used long term can also cause weight gain.67 SSRIs can cause delayed ejaculation in men and anorgasmia in women (5HT2A spinal cord receptors may inhibit orgasm and ejaculation).68 SSRIs are remarkably less likely than TCAs to be life-threatening when ingested in fairly high overdoses.69 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, and the other with citalopram hydrobromide. Although these agents are said to be relatively free of major cardiovascular risks,70 they are not totally devoid of cardiovascular effects, especially in patients suffering from cardiovascular disease.71 Cardiovascular effects of SSRIs (Table 8), 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 ECG PR, QRS, or QTc intervals.72 However, there are case reports of prolonged QTc intervals, first-degree block, and orthostatic hypotension in SSRI-treated patients.71 These agents may cause myocardial ischemia secondary to serotonin’s vasoconstrictive effects on damaged endothelium.73 The identification of an association between fenfluramine hydrochlorides and valvular disease raised a similar possibility with SSRIs. Among a large consecutive cohort of patients taking SSRIs, prevalence of mitral and aortic regurgitation was Curr Probl Cardiol, May 2002

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no different from that of control participants.74 Detailed cardiovascular effects of each agent are discussed individually. SSRIs and cardiovascular drug interactions are reviewed in Tables 6, 8, and 9. Citalopram hydrobromide. Citalopram hydrobromide is structurally unrelated to any TCAs, tetracyclics, or to any other antidepressants. It is a mixture of an S and an R enantiomer. It is the latest of SSRIs approved for treatment of depression. It has been used for many years in Europe before being approved in the United States. Unlike other SSRIs, it is relatively selective for serotonin reuptake inhibition.40 It has low or no affinity for 5HT1A, 5HT2A, D1, D2, ␣-1, ␣-2, ␤-adrenergic, H1, muscarinic, or cholinergic receptors. Citalopram hydrobromide is typically started in the patient (10 to 20 mg/d) once daily in the morning and has a maximum daily dose (60 mg/d). Although citalopram hydrobromide does not cause significant QTc or ECG changes, it can cause a decrease in heart rate.75 It has no effect on blood pressure,76 nor does it cause significant orthostatic hypotension. Tachycardia and postural hypotension have been described in approximately 1% of cases.29 Infrequent side effects may be hypertension, bradycardia, cerebrovascular accident, and MI. Rare incidents of transient ischemic attacks, phlebitis, atrial fibrillation, cardiac arrest, and bundle branch block have been described with an incidence of less than 1 in 1000. It has not been studied systematically in patients having cardiovascular disease. In a summary review of citalopram hydrobromide overdoses,72,73 5 Swedish cases were known to have ingested more than 1900 mg of citalopram hydrobromide (almost 100 times the usual dose) and all these patients had either conduction delay or seizures. Among 18 patients who ingested 600 to 1900 mg, 6 experienced QRS widening.72 There was only 1 reported death from an overdose of citalopram hydrobromide alone.72 Important drug interactions with citalopram hydrobromide are summarized in Table 9. S-Citalopram, not yet approved by the FDA, seems to be a more selective SSRI than the parent compound, which is a racemic mixture. S-Citalopram is considered to be the active ingredient for mixed racemic citalopram’s antidepressive action. In vitro studies demonstrate that S-Citalopram has a better pharmacokinetic drug interaction profile than the parent compound. Some recent studies also suggest that S-Citalopram might be more effective than racemic citalopramhydrobromide77 and may have a better antianxiety profile as well. Fluoxetine. Fluoxetine is also chemically unrelated to TCAs. In addition to its SSRI action, it possesses some norepinephrine reuptake and 5HT2c agonist action.40,78 It was the first SSRI approved for major 214

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depression in the United States. It is indicated for treatment of major depression, bulimia nervosa, obsessive-compulsive disorder, and premenstrual dysphoric disorder. Fluoxetine is best prescribed as a single morning dose (10-80 mg/d). Fluoxetine does cause mild bradycardia,79 more so in elderly patients with preexisting cardiac arrhythmias. There are reports of fluoxetine having vasoconstrictive effects on damaged endothelium of patients with coronary artery disease, which may cause angina.73 Roose et al80 showed that fluoxetine seemed to be a relatively benign treatment for depressed patients with cardiovascular diseases. Fluoxetine has negligible effects on both resting and postural blood pressure, even in patients with impaired left ventricular function, and does not seem to affect conduction, even in patients with preexisting conduction disease. There is one report of fluoxetine-induced atrial fibrillation in an elderly patient.81 Fluoxetine has been associated with decreased plasma glucose levels and hyponatremia (seen with other SSRIs) in patients receiving diuretic drugs.82 Fluoxetine can increase blood levels of other drugs (Table 9) because of its long plasma half-life70 and inhibition of the cytochrome P-450 2D6 isoenzyme. In the largest series of overdose cases,83 the authors reported incidents of sinus tachycardia, trigeminy, and junctional rhythms with doses as high as 1500 mg fluoxetine alone. Despite these case reports, fluoxetine has very few documented adverse cardiovascular effects. Of approximately 15,000,000 estimated treatment cases, there were only approximately 5,000 reports of adverse cardiovascular effects. These effects included ECG abnormalities, thrombophlebitis, and other cardiovascular events, which may or may not have been because of the direct effect of fluoxetine. Thus, the incidence of adverse cardiovascular events with fluoxetine is under 0.0003%.84 More recently, long-acting weekly fluoxetine (Prozac weekly) has been introduced. This is a delayed-release formulation, containing entericcoated pellets of fluoxetine hydrochloride equivalent to 90 mg fluoxetine. Weekly dosing of fluoxetine appears to be well-tolerated and is probably as effective as daily dosing for treatment of depression.85 Adherence with once weekly fluoxetine was superior to that of once-daily dosing in 1 study.86 Before weekly fluoxetine is started, patients should be stabilized on daily (20 mg) fluoxetine. Once fluoxetine daily is working and symptoms are 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 belongs to a new chemical series of aralkylketones, chemically unrelated to other SSRIs. In addition to its Curr Probl Cardiol, May 2002

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SSRI activity, it also possesses some ␴ actions, the role of which are not clear. This agent was approved in 1995 for obsessive-compulsive disorder. Fluvoxamine is typically prescribed twice per day (50-400 mg/d). There are no significant ECG changes reported with fluvoxamine except some ST-segment changes, the occurrence of which are less than 1%, and atrioventricular and supraventricular block that occurs in less than 1 per 1000 cases treated.29 Cases of hypertension, hypotension, syncope, and tachycardia are described in approximately 1% of patients. There are also 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 of 310 had sinus bradycardia develop.87 Fluvoxamine has not been extensively studied for its cardiovascular effects or in patients with concomitant cardiac disease. Like other SSRIs, it seems to be relatively cardiosafe. Fluvoxamine can potentate activity of warfarin, theophylline, and propranolol (Table 9) because it inhibits hepatic P-450 enzymes 1A2, 2C9, 2C19, and 3A4.87 For this reason, coadministration of terfanadine, astenizole, and cisapride is contraindicated.29 Paroxetine hydrochloride. Paroxetine hydrochloride is an SSRI that is unrelated to other TCAs and tetracyclics. It possesses muscarinic/ cholinergic antagonist actions and norepinephrine reuptake inhibition (NRI), in addition to its SSRI properties. It has little affinity for 5HT1, 5HT2, H1, D2, ␤-adrenergic, ␣-1, or ␣-2 receptors. Paroxetine hydrochloride has a short half-life, which can result in some withdrawal symptoms if stopped suddenly. Paroxetine hydrochloride is taken once daily (10-50 mg/d). Tachycardia has been described in 12% of patients receiving this drug in 1 clinical trial.88 In other clinical trials, tachycardia, hypertension, and syncope are described in approximately 1% of the population. Infrequent side effects also include bradycardia, hypertension, and hypotension.29 Vasodilation is reported with a frequency of 4%. Thrombophlebitis and vascular headache are listed as rare side effects. Direct cardiac effects, which are described as rare, are CHF, MI, and angina pectoris.29 Similar to fluoxetine, studies in patients with cardiovascular disease have demonstrated that paroxetine hydrochloride was associated with a low incidence of adverse effects.89 In the same study, there was mild bradycardia, which disappeared later during treatment. Paroxetine hydrochloride does not have any clinically sustained effect on heart rate; diastolic, systolic, supine, or standing blood pressure; cardiac conduction; or ventricular ectopic activity. It does not have significant effect on ECG. 216

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Overall, paroxetine hydrochloride appears to have a benign cardiovascular profile.89,90 It does cause unfavorable interactions with other drugs that are summarized in Table 9.

Sertraline Hydrochloride Sertraline hydrochloride is chemically unrelated to TCAs or other SSRIs. It has dopamine reuptake inhibitor action and has ␵ actions, in addition to serotonin reuptake inhibition. It does not have any significant affinity for adrenergic (␣-1, ␣-2, and ␤), cholinergic, ␥ aminobutyric acid, dopaminergic, histaminergic (H1), serotonergic (5HT1A, 5HT1B, and 5HT1C), or benzodiazepine receptors. Sertraline hydrochloride is approved for depression, panic disorder, obsessive-compulsive disorder, and posttraumatic stress disorder. Sertraline hydrochloride has less of an effect on the cytochrome P-450 system than other members of the SSRI class. A “serotonin syndrome” has been described in overdose with sertraline hydrochloride and other SSRIs, characterized by tachycardia, coma, hypertension, hallucinations, tremor and skin flushing, and hyperthermia.89-91 Sertraline hydrochloride does not have any significant effects on ECG. Tachycardia is seen in less than 1% of the treated population.29 Vascular effects of sertraline hydrochloride include infrequent hypertension and postural hypotension, and, rarely, cerebrovascular accidents or aggravation of hypertension. Direct cardiac effects include an approximate 1% occurrence of chest pain, palpitations, rare precardiac chest pain, and MI.28 Of SSRIs, sertraline hydrochloride may have the least interactions with commonly used medications as described in Table 9. Sertraline hydrochloride is typically prescribed as a once-morning dose (25-200 mg/d). Sertraline hydrochloride is an effective treatment for depressed patients with cardiovascular disease. In 1 study,92 sertraline hydrochloride was used to treat depressed patients with ischemic heart disease and it did not show any significant effect on heart rate or supine or standing systolic or diastolic blood pressure. The drug has also been shown to relieve noncardiac chest pain.93 Recently it was reported that sertraline was shown to be cardiosafe as placebo in 400 post-MI patients monitored up to 6 months immediately after a heart attack. This study was insufficiently powered to demonstrate a cardioprotective effect of sertralines, but the data was suggestive. Further studies will be required to see whether treatment of depression in patients with cardiovascular disease can reduce the risk of cardiovascular events. It has been reported that depressed patients exhibit increased platelet activation and enhanced procoagulant properties over healthy control participants.94 Modulation of platelet Curr Probl Cardiol, May 2002

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activity has been suggested as a potential mechanism responsible for reduction of cardiovascular mortality in major depression after therapy with SSRIs.94,95 If this turns out to be the case, cardiologists may soon be treating depression with antidepressants as a primary cardiovascular risk reduction strategy.96

Newer Antidepressants with Unique Chemical Structures Members of this group of antidepressants have novel and generally unrelated mechanisms of actions and unique effects and side– effect profiles. Comparative reviews of these drugs are featured in Tables 6 and 8. Common drug interactions with members of this group are listed in Table 10. Venlafaxine hydrochloride. Venlafaxine hydrochloride97,98 is a unique antidepressant with dual mechanisms of action.99 The agent blocks reuptake of serotonin and norepinephrine at relevant doses in human beings.99 It also possesses weak dopamine reuptake properties at higher doses.100 Venlafaxine hydrochloride has no significant affinity for muscarinic/ cholinergic, histaminergic (H1), or ␣-adrenergic receptors. It is approved for treatment of depression and generalized anxiety disorder. Because it has a short half-life, venlafaxine hydrochloride is prescribed twice or 3 times per day (25-375 mg/d). As an extended-release preparation, it can be prescribed once per day (75-225 mg/d). Conduction abnormalities of venlafaxine hydrochloride did not differ when compared with placebo.29 There is a mean change from baseline of QTc 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 blood pressure, especially in higher doses,101 and this increase in blood pressure is statistically significant in doses higher than 300 mg/d.102 In placebo-controlled studies, clinically significant increases in blood pressure (increase in diastolic pressure ⱖ15 mm Hg to ⱖ105 mm Hg from baseline) were observed in 5.5% of patients at doses above 200 mg/d; the mean increases was 7 mm Hg after 6 weeks of treatment with doses above 300 mg/d.102 Venlafaxine hydrochloride increases heart rate significantly when compared with placebo.29 The mean increase is 4 bpm relative to baseline, therefore caution should be exercised in patients whose underlying medical conditions might be compromised by an increase in heart rate (eg, patients with hyperthyroidism, heart failure, or recent MI), particu218

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larly 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 less than 1% of patients, and mitral valve disease, as a complication, is rare. Many of these cardiovascular effects are attenuated when patients are switched to extended-release preparation. Drug interactions with venlafaxine hydrochloride are described in Table 10. Bupropion hydrochloride. Bupropion hydrochloride is an aminoketone and has a unicyclic structure chemically unrelated to any other antidepressants. It is structurally related to amphetamines. The antidepressant effects of bupropion hydrochloride appear related to both NRI and dopamine reuptake inhibition. It is also postulated that its dopaminergic actions account for its effectiveness as an antismoking agent. Bupropion hydrochloride is typically prescribed in 3 divided doses within a daily range (75-450 mg/d). Slow release preparation can be prescribed twice per day (100-400 mg/d). Unlike SSRIs, bupropion hydrochloride does not produce significant sexual side effects because it lacks serotonin activity. In fact, bupropion hydrochloride is sometimes used effectively to treat the sexual side effects so common with SSRIs. Bupropion hydrochloride also has an appetite-suppressant action that makes it contraindicated in patients with active bulimia.32,55 It can also lower seizure threshold, which is why there is a relative contraindication to its use in patients with seizure disorder. This increased risk of seizures seems to be attenuated when slow release preparation is used. Bupropion hydrochloride is also used as an antidepressant augmentation agent when combined with other SSRIs to treat refractory cases of depression. It has also shown promise in patients with attention deficient hyperactivity disorders because of its stimulant-like activity. Bupropion hydrochloride, compared with TCAs, is relatively less cardiotoxic. In 1 study,103 bupropion hydrochloride showed no problems with conduction, contractility, or orthostatic hypotension in patients with preexisting cardiac diseases. Palpitations are reported in 2% of cases,29 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 hydrochloride has been reported to elevate blood pressure occasionally,29 but does not affect on heart rate. Bupropion hydrochloride is also an effective agent for facilitating smoking cessation.104,105 When used as either an antidepressant or antismoking agent and combined with a nicotine transdermal system, incidence of hypertension is increased to as high as 6.1%.29 Therefore, Curr Probl Cardiol, May 2002

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blood pressure should be monitored carefully if both bupropion hydrochloride and nicotine replacement strategies are used simultaneously. The cardiac safety of bupropion hydrochloride when used alone, and its effectiveness as both an antidepressant and antismoking agent, makes this medication unique among all antidepressants. If further studies replicate these findings, bupropion hydrochloride could become a preferred choice among cardiologists for depressed patients who have cardiovascular risk or disease, smoke, or both. In addition, several studies are currently underway to determine whether either bupropion hydrochloride or sertraline hydrochloride removes depression as a primary risk factor for cardiovascular disease, and to determine their relative safety in patients with existing cardiovascular disease. If this research shows a benefit, it is likely that both these antidepressants will be the first psychotropic drugs used to reduce depression as a primary risk factor for heart disease.96 Drug interactions with bupropion hydrochloride are described in Table 10. Trazodone hydrochloride and nefazodone hydrochloride. Trazodone hydrochloride and nefazodone hydrochloride have different structures from TCA and MAOI antidepressant drugs. These agents are sibling compounds, coming from the same class of antidepressants, serotonin 2A antagonist/reuptake inhibitors. Trazodone hydrochloride acts by a potent blockade of 5HT2A receptors, combined with a less potent serotonin reuptake inhibitor action. It also has antihistamine properties and ␣-1 antagonist action. Trazodone hydrochloride, when used as an antidepressant, is prescribed in divided daily doses (50-600 mg/d). When it is used as a sleep aid or as adjunctive antidepressant, it is typically prescribed (50-200 mg) at bedtime. Trazodone hydrochloride lacks the quinidinelike properties of TCAs and lacks major effects on cardiac conduction. However, it can cause rare ventricular ectopy, including ventricular tachycardia.106 Major cardiovascular toxicity seen with trazodone hydrochloride is postural hypotension, which may be associated with syncope. Risk of hypotension can be less if the drug is taken with meals. Trazodone hydrochloride can cause priapism, which requires discontinuation of the drug and emergency intervention.51,107 Nefazodone hydrochloride acts by blocking 5HT2A receptors, and is not very potent as a serotonin reuptake inhibitor. In addition, it causes weak NRI. It does not have significant affinity for ␣-1 and ␤-adrenergic, 5HT1A, cholinergic, dopaminergic, or benzodiazepine receptors. Nefazodone hydrochloride is prescribed in divided doses with a daily range (100-600 mg/d). In January 2002, the FDA and Bristol Myers Squibb (manufacturer) issued a block box warning that nefazodone, in rare cases, 220

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has caused liver failure leading to either liver transplantation or death. Compared with trazodone hydrochloride, it causes a lower frequency of orthostatic hypotension and priapism108 and has less anticholinergic and ␣-adrenergic blocking activity. Reported frequency of orthostatic hypotension is 2.8% and bradycardia l.5%; no other ECG changes have been described.109 There is a statistically significant difference between placebo and nefazodone hydrochloride regarding bradycardia, the clinical significance of which is not clear. Ventricular extrasystoles are infrequent, whereas occurrence of atrioventricular block is less than 1 in 1000.29 Hypertension and syncope are infrequent. Direct cardiac effects include angina pectoris, which is reported at a frequency of less than 1 in 100, whereas CHF is very rare. Because nefazodone hydrochloride can interfere with 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.13 Digoxin levels should also be monitored if nefazodone hydrochloride is taken concurrently, because both drugs are protein bound. Nefazodone hydrochloride does not appear to influence warfarin levels.110 These effects are summarized in Table 10. Mirtazapine. Mirtazapine has a tetracyclic chemical structure unrelated to SSRIs, TCAs, or MAOIs. The mechanism of action is not by serotonin reuptake blockade like SSRIs,111 but it has an antagonist action at central presynaptic ␣-adrenergic inhibitory autoreceptors and heteroreceptors, which increases central noradrenergic and serotoninergic activity. It is a potent antagonist of 5HT2 and 5HT3 receptors and has no significant affinity for 5HT1A and 5HT1B receptors.40 Mirtazapine, because of it sedating effect, it typically prescribed once daily at bedtime (15-45 mg/d). Mirtazapine is not associated with clinically significant ECG abnormalities. Infrequent side effects include ventricular extrasystoles and bradycardia; atrial fibrillation is rare. Direct cardiac effects include a low incidence of MI, angina pectoris, and, rarely, left-sided heart failure has been reported. The drug blocks H1 receptors, which explains its prominent sedative effects and probably the associated weight gain. It has moderate peripheral ␣-blocker activity, which can result in a 7% incidence of orthostatic hypotension.29 Therefore, mirtazapine should be used with caution in patients who have cardiac illnesses that can be aggravated by hypotension. There is some evidence that this agent has a faster onset of action compared with SSRIs.111 Mirtazapine does not cause a significant increase in blood pressure, but can increase heart rate, which can be Curr Probl Cardiol, May 2002

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explained by its mild anticholinergic activity. It is a relatively newer antidepressant and has not been studied in patients with concomitant cardiac disease. Drug interactions with mirtazapine are summarized in Table 9. Reboxetine. Reboxetine is the first selective NRI that, as of this writing, has not been approved for release by the FDA. Reboxetine has no effect on dopamine or serotonin reuptake. It has been shown to be more effective in relieving impaired social functioning and targets symptoms such as tiredness, fatigue, psychomotor retardation, and apathy. It has negligible affinity for adrenergic, histaminergic, muscarinic, dopaminergic, or serotonergic receptors. Dry mouth, insomnia, sweating, and constipation are commonly reported side effects, although they tend to be mild to moderate and transient in nature.112 In 1 study of reboxetine, using approximately twice the recommended dose, it did not significantly prolong QTc. It did, however, increase heart rate by 8 to 11 bpm.113

Antianxiety Agents Benzodiazepines are chemically related and are used as primary agents to treat anxiety syndromes. However, they are increasingly being used as adjunctive or secondary agents, replaced by SSRIs, or both. Most SSRIs have both an antidepressant and antianxiety spectrum of activity and have FDA indication for treatment of both conditions. SSRIs, as a first-line treatment for anxiety disorders, are preferred over benzodiazepines to avoid risk of addiction or withdrawal reaction. Benzodiazepines and SSRIs are used to treat anxiety disorders that include panic attacks and agoraphobia, social phobia, generalized anxiety disorder, obsessivecompulsive disorder, and posttraumatic stress disorder. Benzodiazepines are often the preferred medication to treat situational anxiety or other intermittent subsyndrome anxiety symptoms. In general, benzodiazepines should not be used alone in the depressed patient as they can increase the risk of suicide.30,42 Benzodiazepines are also used as anticonvulsants and skeletal muscle relaxants, and are used to treat akathisia in patients taking antipsychotic drugs. In addition, they are used as part of treatment of some sleep disorders and are commonly used to treat alcohol withdrawal syndromes. Benzodiazepines have extremely favorable cardiovascular side-effect profiles. Their effects on the cardiovascular system include a slight decrease in blood pressure and left ventricular work. They are not 222

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involved in any major interactions with cardiovascular drugs, except for increasing plasma digoxin levels. All these agents can be associated with tolerance and dependency. The subclassification of benzodiazepines include those medications that are long-acting and short-acting. Among long-acting benzodiazepine drugs are chlordiazepoxide, prazepam, diazepam, chlorazepate, halazepam, flurazepam hydrochloride, quazepam, and clonazepam. These drugs require less frequent dosing and have fewer withdrawal problems, but they can accumulate in the body to cause lethargy and marked sedation, especially in the elderly. Among shorter-acting benzodiazepines are the agents oxazepam, temazepam, lorazepam, and those with the shortest half-life, estazolam, triazolam, and alprazolam. These agents do not significantly accumulate, and therefore cause less daytime drowsiness after bedtime dosing. However, because of their shorter half-life, these drugs require more frequent dosing and may be associated with withdrawal symptoms. Other antianxiety agents that are rarely used today because of a higher abuse potential and lower therapeutic index include meprobamate, glutethimide, metprylon, and ethclorvynol. Buspirone hydrochloride is an azapirone and an antianxiety medication unrelated to benzodiazepines or any of the other antianxiety drugs listed above. It acts on the 5HT1a receptor, and unlike benzodiazepines, does not affect the ␥ aminobutyric acid system.114,115 It is relatively short acting, requiring thrice-daily dosing.116-118 It also takes approximately 3 weeks to achieve anxiolysis. It is used for treating generalized anxiety117 and for treatment of mixed anxiety and depressive symptoms. Buspirone hydrochloride is also sometimes used to augment antidepressants because it has some antidepressant (serotonergic) activity.114,119 It has also been used to treat sexual side effects of SSRIs.40 It has no known cardiovascular toxicity, but it has been reported to increase the effects of warfarin. ␤-Adrenergic blockers such as propranolol and atenolol have been used to block secondary effects of anxiety such as muscle tremors, tachycardia, and hypertension. They are not known to produce a true central antianxiety effect.120 Zolpidem tartrate (Ambien) and zaleplon (Sonnata) are principally hypnotics that interact with type 1-benzodiazepine receptors. They have poor antianxiety and muscle relaxant properties and are used for short-term treatment of insomnia. They are both relatively cardio-safe. Zolpidem tartrate can cause palpitations and zaleplon can produce peripheral edema. Curr Probl Cardiol, May 2002

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Antimanic Agents Lithium, the lightest solid element, is a psychoactive agent in the form of a singly charged ion. It was approved in the United States as a first-line agent for mania in l970. A variety of neurobiologic effects of lithium have been proposed to explain its therapeutic action, none of which have been conclusively shown to be the mechanism. Lithium is used as the agent of choice in acute mania and as a bipolar disorder prophylactic agent.121 It has also been used in unipolar disorder prophylaxis and for patients with bulimia, violence, alcohol abuse, and schizoaffective disorders.42,43 Serious potential side effects include neurotoxicity (tremor, mild EPS, papilledema, delirium, and coma), renal side effects (polyuria or nephrogenetic diabetes insipidus), hypothyroidism, and teratogenicity.42,43 Many patients treated with lithium will have ECG changes such as T-wave flattening or inversion and widening of QRS complex develop. These changes do not correlate with serum lithium levels, are reversible with drug discontinuation, and appear to be benign. These ECG changes may be similar to those caused by hypokalemia.1 At toxic lithium levels, reported ECG changes include ST-segment depression and QT prolongation.43 Arrhythmias, when they have been reported, are almost always described in patients with preexisting cardiac disease. This includes sinus node block and tachycardia, which can present in patients as syncope, dizziness, or palpitations. These effects are reversible when lithium is discontinued. Patients with previous sinus node disease can receive lithium, but only with a pacemaker in place. Ventricular arrhythmias are rarely seen, and may be caused by concomitantly used psychoactive medications. There is a small incidence of sudden death in patients with known cardiac disease123 when lithium is combined with other psychotropics, which together can prolong QTc interval. A baseline ECG is recommended for all patients who are being considered for lithium who are older than 40 years, or those with a known cardiac history. While in treatment, follow-up ECGs should be performed periodically. Patients on lithium should be alerted to symptoms of dizziness, palpitations, or irregular heart beats that may suggest a lithium-induced toxicity. The drug should not be used in patients with acute MI. Any patient condition that leads to sodium depletion can raise serum lithium levels into toxic range. Sodium-wasting diuretics such as thiazides, spironolactone, and triamterene can cause increases to toxic lithium 224

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levels. Patients with CHF and decreased renal blood flow can have an increase in lithium levels. Osmotic diuretics that increase renal flow can cause a decrease in serum lithium levels. Other adverse effects of lithium include ankle edema that is responsive to diuretic therapy. The drug-drug interactions with lithium are summarized in Table 13.

Anticonvulsants as Antimanic Agents Anticonvulsants valproic acid, carbamazepine, lamotrigine, gabapentin, topiramate, tiagabine hydrochloride, and benzodiazepine clonazepam, and atypical antipsychotics such as olanzapine, are all used as alternatives to lithium or as adjunctive therapies for treatment of bipolar spectrum disorders.124 Valproic acid. Valproic acid, most typically prescribed in the form of divalproex sodium-coated particles in a capsule, is the only anticonvulsant that has FDA approval for treatment of bipolar disorder.29 Potential serious side effects from valproic acid are pancreatitis, teratogenicity, and hepatotoxicity. Hepatotoxicity can be fatal in children especially under the age of 2 years. If this occurs in adults at all, it is typically the result of polypharmacy with 2 or more potentially hepatotoxic medications. In general, this medication has relatively benign cardiovascular effects and no typical ECG changes are described. Adverse cardiovascular effects with a 1% to 5% frequency are hypertension, palpitations, tachycardia, and chest pain.29 Risk of peripheral edema is 3% to 8%, and bradycardia is reported at a less than 1% frequency.29 Valproic acid has many potential interactions with cardiovascular medications. The most common include: (1) cholestyramine, which can reduce absorption of valproic acid and therefore this anticonvulsant should be administered 2 hours before or 6 hours after cholestyramine; (2) salicylates, which can displace valproic acid from protein binding sites and elevate valproic acid levels; and (3) valproic acid, which can inhibit metabolism of some drugs, such as nimodipine, and increase levels leading to nimodipine toxicity. Carbamazepine. Carbamazepine is often used as a second or adjunctive agent in combination with lithium or valproic acid for treatment of refractory bipolar disorder. It has a black box warning for aplastic anemia,29 which make it imperative that careful pretreatment and biweekly blood counts are performed for the first several months. Carbamazepine can cause AV conduction delays and bradyarrhythmias at therapeutic doses.42,43,125,126 Its vascular effects include hypotension, aggravated hypertension, edema, thrombophlebitis, and thromboembolism. Reported direct cardiac effects include worsening coronary artery disease, CHF, and myocardial infraction. Carbamazepine interacts with Curr Probl Cardiol, May 2002

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TABLE 13. Drug-drug interactions with lithium Class and generic name

Effect on plasma lithium concentration

Digoxin

Unknown

Angiotensin-converting enzyme inhibitors Angiotensin 2 receptor antagonist (Losartan)

Increase by sodium depletion Probable increase lithium via reduce renal clearance

Calcium channel antagonists Diltiazem hydrochloride and verapamil hydrochloride NOT dihydropyridines (eg, nifedipine etc.) Methyldopa Diuretics Carbonic anhydrase inhibitors (Acetazolamide) Loop Diuretics Furosemide

Ethacrynic acid Distal tubule diuretics Thiazides

Metolazone Chlorthalidone Osmotic diuretics Mannitol Urea Potassium-sparing diuretics Triamterene Spironolactone Amiloride Xanthines Theophylline Caffeine

Significance Rare: central nervous system confusion and bradycardia Possible lithium toxicity moderate renal insufficiency Possible lithium toxicity

Decrease or increase lithium levels

Possible lithium toxicity and cardiac toxicity

Unknown

Possible lithium toxicity

Decrease

Increase in lithium excretion

Probable increase lithium by decrease renal excretion Probable decrease renal excretion

May increase lithium concentration

Increase by sodium depletion and decreased lithium clearance Increase Increase

Well documented interaction with an increase in lithium concentrations and possible lithium toxicity

Decrease Decrease

Increase in lithiumm excretion

Increase

May increase lithium concentration

Increase Unclear

Decrease Decrease

May increase lithium concentration

May be used to treat lithiuminduced polyuria Increase in lithium excretion Can decrease lithium concentrations

Adapted from Nurenberg JR, Frishman WH. Cardiovascular considerations with use of psychoactive medications. In: Frishman WH, Sonnenblick EH, editors. Cardiovascular pharmacotherapeutics. New York: McGraw Hill; 1997 p 1049.

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many cardiovascular medications, producing varied drug interactions, some of which include: (1) In combination with adenosine, TCAs, or other quinidine-like drugs, it can produce fatal heart block, MI, or both.13,29,31 (2) By enzyme induction, carbamazepine reduces efficacy of calcium channel blockers (felodipine and nimodipine), disopyramide, and warfarin.13,29,31 Other calcium channel blockers (diltiazem hydrochloride and verapamil hydrochloride) and ticlopidine hydrochloride inhibit metabolism of carbamazepine and can cause carbamazepine toxicity.13,29,31 (3) Colestipol hydrochloride can decrease absorption of carbamazepine.29,31 (4) Carbamazepine used with diuretics increases risk of severe hyponatremia.29,31 Clinical use of other anticonvulsants as primary or adjunctive treatment for mood disorders is common. Anticonvulsants being studied include gabapentin, lamotrigine, tiagabine hydrochloride, toprimate, and trileptal. Gabapentin is the most widely used of these medications but has very questionable efficacy for mood disorders. It is generally the most cardio-safe medication within this anticonvulsant class, with bradycardia as the only reported cardiovascular side effect. Toprimate has the most promise of these anticonvulsants for being an effective adjunctive agent for treatment of bipolar disorder127,128 and may have potential for first-line drug choice. Its principle side effects are central nervous system symptoms and a dose-related weight loss. There is significant interest in its weight-loss-inducing properties, as many psychotropics produce significant weight gain, which might theoretically be reversed with the addition of toprimate. Toprimate can cause hypotension and hypertension, and causes a 12% decrease in digoxin levels.29,31 As a group, lamotrigine, tiagabine hydrochloride, and trileptal tend to produce central nervous system side effects and few cardiovascular effects. Those infrequent cardiovascular effects reported in this drug group include palpitations, hypotension, hypertension, tachycardia, and bradycardia.29,31 Rare cardiovascular events seen with these medications include angina, cerebral ischemia, MI, atrial fibrillation, phlebitis, and hemorrhage.29,31 Clonazepam is frequently used as part of an initial treatment of the manic phase of bipolar disorder or in combination with another mood stabilizer. Similar to other anxiolytics, there is no known cardiac toxicity with clonazepam.42,43 The calcium-channel blocker verapamil hydrochloride has been used as an adjunctive treatment with antidepressants and has also been used, with a limited effect, as a treatment for manic disorders129 when other antimanic drugs are ineffective. When used with lithium, the combination Curr Probl Cardiol, May 2002

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has been associated with enhanced atrioventricular block.130 Verapamil hydrochloride is also an arterial vasodilator. Therefore, it can potentiate hypotension when combined with concurrent antihypertensive treatments, TCAs, MAOIs, and antipsychotics.

Antiobsessional Medications Treatment of patients having obsessive-compulsive disorder may be caused by a dysregulation of serotonin and dopamine neurotransmission in the brain. SSRIs previously described131,132 are first-line treatment for these disorders. To treat obsessive-compulsive disorder, SSRIs are typically used in higher doses (eg, 60-80 mg fluoxetine) and for longer periods (12-16 weeks) compared with their typical use when treating depressions.42,43 As discussed with SSRIs, there is little serious cardiotoxicity with these medications. Clomipramine hydrochloride,134-136 a TCA, is also a very effective antiobsessional agent that has the usual spectrum of cardiac toxicity described earlier for drugs of this class, but in general it causes less cardiac toxicity.

Clinical Consideration in Patients with Heart Disease Anxiety and depression are very common in patients with cardiovascular disease.8,135-137 There is now significant evidence that depression may be a primary cardiovascular risk factor for coronary artery disease3-7,48 and hypertension.138 Depression has also been shown to inhibit a patient’s success rate for smoking cessation11 and other healthy lifestyle changes. It is still uncertain whether treating patients with antidepressants reverses effects of depression on cardiovascular risk. However, treating patients with antidepressants, in general, improves patient adherence to medical recommendations. In addition, the antidepressant bupropion hydrochloride has been shown to be an effective agent in treating both depression and smoking cessation. Phobic anxiety has also been linked to sudden death8 and chronic anxiety may exacerbate other chronic cardiovascular risk factors, most notably hypertension.8 Psychosis is seen in patients with cardiac disease. It is therefore important to consider cardiovascular effects of psychoactive medications not only in patients free of cardiovascular disease, but especially in patients with preexisting cardiovascular disease. The most significant deleterious cardiac effects of psychoactive medications have been well described with older medications (phenothiazines, MAOIs, and TCAs). Our experience with newer antidepressants and atypical antipsychotics is evolving. In general, these newer medications appear to be more cardio228

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safe than older medications. Significant interest and potential risks of QTc prolongation of many new psychotropic medications are emerging. These effects may be especially dangerous when QTc-prolonging effects of 2 or more medications are additive.

Hypotension/Hypertension Antipsychotic medications, particularly low-potency phenothiazines and atypical medications, can cause significant hypotension. This risk of hypotension is highest with chlorpromazine and thioridazine. Hypotension caused by atypical medications, from the greatest to lowest frequency, include clozapine 9%, quetiapine 7%, and risperidone and olanzapine 5%; the least hypotensive effects are reported with ziprasidone and haloperidol (1%). Psychotropics in combination with cardiovascular medications such as methyldopa, diuretics, ␣-adrenergic blockers, calcium antagonists, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and nitrates may aggravate hypotensive blood pressure effects. Hypertension is not a contraindication to use of psychoactive medications. Some antipsychotic medications, however, can infrequently cause hypertension. The most likely atypical antipsychotics to cause hypertension, from the greatest to lower risk, include clozapine 4%, olanzapine 2%, ziprasidone 1%; the lowest risk of hypertension (⬍1%) is caused by risperidone and quetiapine. TCAs can interfere with hypotensive actions of clonidine hydrocloride, guanethidine monosulfate, and others. MAOIs, TCAs, trazodone hydrochloride, nefazodone hydrochloride, and most atypical medications can cause orthostatic hypotension. The only newer antidepressants that can cause a significant frequency of hypertension is venlafaxine hydrochloride when it is taken in doses greater than 200 mg/d. This may not be an important effect if extended release preparation is used.29 In choosing a psychoactive medication for the hypertensive patient, it is best to use those drugs that cause less or no postural hypotension (eg, butyrophenone or perhaps ziprasidone for psychosis and major tranquilization; a SSRI or bupropion hydrochloride for depression).

Congestive Heart Failure Depression is common in patients with CHF and is a negative prognostic factor regarding morbidity and mortality.139-144 There is no evidence as yet that treatment with antidepressants can change the natural history of heart failure patients. Some phenothiazines have been shown to have direct myocardial depressant activity or vasodilator effects that Curr Probl Cardiol, May 2002

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would probably counteract any major hemodynamic deterioration in patients.145 Therapeutic doses of atypical antipsychotic drugs do not seem to have important effects on myocardial function. Some atypical medications report CHF as a direct cardiac effect. This effect has been reported infrequently (1/100-1/1000) with olanzapine29 and rarely (⬎1/1000) with clozapine and quetiapine. Therapeutic doses of antidepressant drugs do not seem to have important effects on myocardial function. However, because patients with heart failure will often be receiving diuretics and multiple vasodilators, postural hypotension could be a problem with concomitant use of low-potency phenothiazines (chlorpromazine has been used as a vasodilator therapy for CHF) or atypical medications. Under these circumstance it might be best to treat with the atypical, ziprasidone, or high-potency neuroleptics, which seem to have less risk of causing postural hypotension. In treating depressed patients with CHF, it might be better to avoid the use of TCAs and MAOIs, and instead use SSRIs and other newer antidepressants, which do not cause significant hypotension.

Angina Pectoris Depression is associated with significantly more limitation, more frequent angina, less treatment satisfaction, and lower perceived quality of life.146 There is no definitive evidence to suggest that any psychoactive medication is dangerous in patients with angina pectoris. However, some antipsychotics can produce significant tachycardia. Clozapine produces tachycardia in 25% of patients. The other atypical medications can cause tachycardia with the following frequencies: quetiapine 7%, risperidone 5%, olanzapine 3%, ziprasidone 2%.22,29 Anticholinergic TCAs, such as amitriptyline hydrochloride, should also probably be avoided in patients with angina pectoris.

Acute Myocardial Infarction Depression has been shown to be a risk factor for MI, and an aggravating factor in survivors of MI.147-156 Studies have shown that SSRIs may be safer48 than other antidepressants in treating depression in patients with MI or who are at risk for MI.89,157,158 Because MI can be complicated by hypotension, heart block, and arrhythmias, psychoactive medications that cause postural drops in blood pressure or enhance cardiac conduction defects should be avoided. One should not combine psychoactive medications with quinidine-like electrophysiologic effects with antiarrhythmic drugs having similar electrophysiologic actions (see Table 4). 230

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Arrhythmias Many phenothiazines (thioridazine, chlorpromazine), some newer atypical antipsychotics (ziprasidone, clozapine), and TCAs have a greater propensity for causing QTc abnormalities.18,19,23,24,44 This probably increases the risk of torsades de pointes and sudden death. However, with newer atypical medications and antidepressants, the weight of available evidence suggests that this is not a common problem when single agents are used alone in therapeutic doses. However, one must be extremely careful of additive effects of prolonging QTc interval when using combinations of medications (Table 4). This is especially true in patients who have existing cardiovascular diseases (Table 5). Under these circumstances, QTc prolongation can exceed 500 ms, leading to a significant risk of torsades de pointes18,24-26 and sudden death. In general, it is fair to say that treatment with agents that affect cardiac conduction should be avoided in patients with known abnormalities of the cardiac conduction system. However, minor disorders of intracardiac conduction, such as isolated left- or right-bundle branch block, are not automatically contraindications to the use of these drugs. Careful cardiac monitoring is warranted. Because lithium can cause sinoatrial node blocks, this drug should be avoided in patients with sinus node dysfunction. Fortunately, valproic acid is an excellent alternative for patient with sinus node dysfunction. Also, cardiovascular toxicities of various psychoactive drugs should be taken into consideration in patients vulnerable to committing suicide.

No Known Cardiac Disease In individuals having no known cardiovascular disease, conventional MAOIs have little use today because of associated postural hypotension and the propensity to hypertension caused by an interaction with tyramine-rich foods. MAOIs are generally contraindicated in patients over the age of 60 years. This situation may change shortly if selective MAO-A and MAO-B inhibitors are developed and released for clinical use. Most other psychoactive medications can be used. In the elderly, however, because of the threat of postural hypotension, phenothiazines, some atypical antipsychotics, clozapine, TCAs, trazodone hydrochloride, and nefazodone hydrochloride should be used with caution.

Conclusion Psychoactive medications are being used frequently by patients, many of whom will encounter practicing cardiologists. In general, newer novel antipsychotic medications have very favorable cardiovascular and adCurr Probl Cardiol, May 2002

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verse effect profiles. New data describing depression as a primary cardiovascular risk factor may lead many cardiologists in the near future to be principle prescribers of newer antidepressants. The cardiologist may also be called on to prescribe other psychoactive medications and must therefore be aware of the potential therapeutic benefits, possible drugdrug interactions, and toxicities related to these treatments. Most newer psychoactive medications used to treat psychosis, depression, bipolar disorders, and obsessive-compulsive disorder still need to be evaluated further in patients with known cardiovascular risk factors or diseases. Furthermore, cardiac monitoring may also be warranted in patients who are on multiple medications that can affect cardiac functioning. It is helpful to build our knowledge base about effects of all psychotropic medications. Cardiologists can assist in this effort by reporting drug-drug interactions or unexpected toxicities, which they observe in their clinical practice.124

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