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Use of cyclic antidepressants in patients with cardiac conduction disturbances
Clinical Problems in Psychiatric Treatment of the Medically Ill Effective psychiatric intervention with the medically ill requires adapting the techniques of psychiatric diagnosis, psychotherapy, and psychopharmacology to each specific medical illness. This section, edited by Barry S. Fogel, M.D. and Alan Stoudemire, M.D., will address diagnostic technologies, special topics in clinical psychopharmacology, and special applications of psychotherapy appropriate to patients with concurrent medical and psychiatric disorders. Articles will review and examine the literature on these topics to derive guidelines for clinical practice.
Use of Cyclic Antidepressants in Patients with Cardiac Conduction Disturbances Alan Stoudemire,
M.D., and Prescott Atkinson,
M.D., Ph.D.
Abstract: Cyclic antidepressants can produce cardiac complications in patients with certain types of cardiac conduction abnormalities. Most cyclic antidepressants have a quinidinelike effect on the heart, which, in combination with Type 1 antiarrhythmic agents such as quinidine, disopyramide and procainamide, may induce heart &lock and potentially lethal arrhythmias in suscepfible individuals. Patients with known cardiovascular disease warrant careful evaluation beforetricyclic therapy is initiated. Guidelines are presented for identifying high-risk patients and for using cyclic antidepressants in patients with cardiac conduction abnormalities.
channels. On account of this effect, CyAD can exhibit significant quinidinelike properties on cardiac conduction and may have additive effects with Type I antiarrhythmic drugs [2I. In medically ill patients with heart disease, the possible effects of CyAD on the heart and interactions with cardiac medications should be considered prior to initiation of therapy. This discussion will focus on quinidinelike effects of CyAD and offer guidelines for the assessment and treatment of depressed patients with cardiac conduction abnormalities.
Since the initial finding by Kuhn in i958 [l] that imipramine improved endogenous depression, the class of drugs known as the tricyclic, tetracyclic, and heterocyclic antidepressants (collectively referred to here as the cyclic antidepressants or CyAD) have become the first-line drug treatment of major depression. In addition to inhibiting presynaptic neuronal reuptake of biogenic amines such as norepinephrine and serotonin, these agents also inhibit transmembrane fast sodium
Normal and Abnormal Cardiac Conduction
We are very pleased to initiate the new section on clinical problems in psychiatric treatment of the medically ill with the paper by Dr. Stoudemire and Dr. Atkinson on the use of cyclic with cardiac antidepressants in patients conduction disturbances. From the Medical Psychiatry Unit, Emory University Hospital and Emory University School of Medicine, Atlanta, Georgia.
General Hospitd Psychiaty 10,389-397, 1988 0 1988 Elsevier Science Publishing Co., Inc.
655 Avenue of the Americas, New York, NY 10010
Under normal conditions, the heartbeat originates in the sinoatrial (SA) node, which is located at the junction of the superior vena cava and the right atrium (Fig. 1) [3]. Impulses originating in this dominant pacemaker spread out and depolarize both atria and reach the atrioventricular (AV) node. Except for the conduction pathway extending from the AV node, located in the right posterior portion of the interatrial septum, the atria and ventricles are electrically isolated from each other by fibrous tissue. The pathway from the AV node is called the bundle of His and extends to the top of the interventricular septum, where it gives rise to the left- and right-bundle branches. The left-bundle
389 ISSN 0163~&P&3/88/$3.50
A.
Stoudemire and I’. Atkinson
-66 RBB
Figure 1. Cardiac conduction system (see text). SAN, sinoatrialnode; AVIV, Atrioventricular node; BH, Bundle of His; LBB, Left bundle branch; and RBB, Right bundle branch; (Adapted from Glassman AH, Bigger JT: Cardiovascular effects of therapeutic doses of tricyclic antidepressants. Arch Gen Psychiatry 38:815-820, 1981.)
branch in turn divides to form the left-anterior and left-posterior fascicles. The right-bundle branch and left fascicles continue subendocardially down the length of the interventricular septum and give rise to the Purkinje fibers of the ventricles, which fan out and rapidly conduct the impulse across the ventricular myocardium. On the electrocardiogram, the interval between the P wave and the QRS complex is the PR interval. The PR interval is measured from the onset of atria1 depolarization (P) to the onset of ventricular depolarization (Q). Its normal duration in adults is 0.12-0.20 seconds. The PR interval is used as a measure of AV conduction time. The PR interval may be subdivided by His bundle electrocardiography into the PA interval (a measure of intraatrial conduction time), AH interval (a measure of AV nodal conduction time), and HV interval (a measure of His-Purkinje conduction time) [4]. The QRS complex (normally 0.04-0.10 seconds) represents the time of ventricular muscle depolarization. The QRS can be prolonged by blocks in the bundle branches, the Purkinje system, or in the myocardium itself. Clinically, bundle branch blocks are particularly common and important. The QT interval is a rough approximation of the refractory
period of the ventricles and is measured from the beginning of the QRS complex to the end of the T wave. The QT interval is rate dependent, and when corrected for rate, is designated the “QT,” interval 151. Cardiac arrhythmias can be due either to abnormalities of impulse generation or to abnormalities of impulse conduction [5]. Many defects involve either abnormalities in the generation of impulses in the SA node or in the conduction pathways to the ventricles [7]. Late emergence or absence of impulses from the SA node is termed SA block. The sick sinus (bradycardia-tachycardia) syndrome refers to sinus node dysfunction, which results in symptomatic bradyarrhythmia, including sinus bradycardia, SA block, or sinus arrest [4]. Atria1 tachyarrhythmias observed in this syndrome include paroxysmal atria1 fibrillation, paroxysmal atria1 flutter, and paroxysmal atria1 tachycardia. If AV conduction is consistent, but the AV conduction time is excessive, first degree AV block is present. First-degree AV block is defined as a prolonged PR interval (greater than 0.20 seconds in adults) with AV conduction intact; P waves are normal, and a QRS complex follows every P wave. Second-degree AV block is a form of AV block with blocked P waves, i.e., P waves that are not transmitted and, therefore, are not followed by a QRS complex. Second-degree AV block can be divided into the relatively benign Mobitz type I (Wenckebach), and the much more ominous Mobitz type II. Mobitz type I (Wenckebach) second-degree block is characterized by progressive lengthening of the PR interval prior to the blocked P wave. Mobitz type II second degree blockis characterized by fixed PR intervals prior to the blocked P wave. Third-degree (complete) heart block is defined by a total lack of conduction between the atria and the ventricles. Third-degree heart block results in complete AV dissociation, with the atial rate usually faster than the ventricular rate. Table 1 summarizes the three degrees of AV block. Defects in the conduction of impulses downstream from the AV node give rise to the various bundle branch blocks (left-bundle branch block, right-bundle branch blocks, and hemiblocks), which announce their presence by characteristic changes in the ECG [4]. Total interruption of conduction can occur at the AV node, the Bundle of His, or within branches of the trifascicular conduction system.
Antidepressants and Cardiac Disease
Table 1. Salient Features
of A-V Block Features
Degree First degree
Prolongation of PR interval beyond 0.20 set Dropped ventricular responses Progressive lengthening of PR intervals until a beat is dropped (Wenckebach phenomenon)
Second degree Type I
Consecutively conducted beats with constant PR intervals before the dropped beat
Type II High-grade or advanced Third degree
Two or more consecutively dropped beats (at norma atria1 rates) Complete AV block: No conducted beats in the presence of a slow ventricular rhythm
(under 45) and ample opportunity for conduction Reproduced with permission from Practical Electrocardiography, by HJL Marriott, The Williams & Wilkins Co., Baltimore, 1972. +50
Table 2. Cardiac Effects of Selected
Antiarrhythmic
Drugs [6, 91 EKG Effects QRS QT,
--FAST
r
Heart block
DW?
PR
Quinidine Disopyramide (Norpace) Procainamide (Pronestyl) Tricyclic Antidepressants
+ + + +
+ 2 + +
+ + + +
+ ? + +
0
0
0
0
+
+
*
+
+ +
0 0
-
+ +
+ +
+ 0
+ +
+ *
+ +
0 0
0 0
+ +
Class I-A
Class I-B Lidocaine (Xylocaine) Class I-C Flecainide (Tambocor) Class II Propranolol (Inderal) Acebutolol (Se&al) Class III Amiodarone (Cordarone) Bretylium (Bretylol) Class IV Verapamil (Isoptin, Calan) Diltiazem (Cardizem)
\ \
Effects listed as “+” are increased or present, as “-I’ are decreased, as “ 2 ” are increased or unchanged (variable), and as “0” are unchanged.
Antiarrhythmic
\” \
Agents and CyAD
Four classes of antiarrhythmic agents have been described, several of which have effects on the heart similar to those of the cyclic antidepressants (Table 2) [6, 8, 91. The first of these, class I agents, e.g., quinidine, lidocaine, and flecainide, depress the fast Na’ channel, which mediates phase 0 of the action potential, the initial rapid depolarization (Fig. 2). Class I drugs have been further subdivided into subclasses A, B, or C depending on their differential effects on fast sodium channels and re-
I
250 TIME (msec)
\c
500
Figure 2. Effects of quinidinelike drugs on the cardiac action potential. Dotted line represents normal action potential, and solid line represents effects on the action potential of quinidinelike agents in slowing the response. Phase “0” is depolarization and rapid reversal of transmembrane potential. In most cardiac cells, phase 0 is generated by the influx of Na’ ions through selected transmembrane channels. Phase 1, 2, and 3 represent repolarization. Phase 4 is the diastolic phase. The Ca‘ + or slow channel is activated during the plateau phase, which allows secondary inward current to flow. These drugs reduce the slope of phase 4 (tending to eliminate ectopic foci), slow the rate of fast depolarization (phase 0), and thus retard impulse conduction and extend the refractory period. (Adapted in part from Bigger JT, Hoffman BF: Antiarrhythmic drugs, In Gilman A, Goodman LS, Rall TW, Murad F (eds): The Pharmacological Basis of Therapeutics, 7th ed. New York, MacMillan Publishing Company, 1985, ch. 31, p. 749.) polarization. Class I-A drugs (quinidine, procainamide, disopyramide, and tricyclic antidepressants) not only depress fast Na* channels, but also prolong repolarization. Class I-B drugs (e.g., lidocaine, phenytoin, tocainide, mexiletine) have minimal phase-O depression and shorten repolarization. Class I-C drugs (e.g., flecainide) depress 391
A. Stoudemire
and P. Atkinson
but have little effect on depolarization, repolarization. Class II antiarrhythmics, e.g., propranolol and acebutolol, work primarily by antagonizing the effects of catecholamines on cardiac beta-adrenergic receptors. Class III antiarrhythmic agents such as amiodarone increase the duration of action potential via sodium channel blockage during phase 2 and part of phase 3 of the action potential. Class IV drugs are calcium channel blockers, (e.g. verapamil, diltiazem), which delay repolarization by inhibiting the slow inward Ca’ +-mediated current. Class IV antiarrhythmics lead to prolongation of the plateau phase (phase II) of the action potential. Some calcium-entry-blocking agents such as diltiazem and verapamil can adversely affect AV nodal function. Because they depress myocardial impulse conduction, drugs with quinidine-like antiarrhythmic activity (e.g., tricyclic antidepressants) affect various ECG parameters [lo]. They often increase the length of the PR, QRS, and QT, segments. Perhaps their most significant effect is the lengthening of the ratio of the effective refractory period (ERP) over the action potential of myocardial fibers; this effect serves to suppress ectopic pacemaker foci that can give rise to atria1 flutter, atria1 fibrillation, ventricular tachycardia, and ventricular premature depolarizations (VPD). These drugs also often cause a rise in heart rate partly because of direct anticholinergic (vagolytic) effects and partly from reflex sympathetic activity induced by their hypotensive a,-antagonist effects. The combined effects of slowed impulse conduction, decreased automaticity, and lengthening of the ERWaction potential ratio in suppressing arrhythmias are complex, and the relative importance of each is not yet fully understood.
Cyclic Antidepressants and Cardiac Conduction In the years since their initial use as antidepressants, CyAD gained anecdotal notoriety for untoward effects upon the heart. There were case reports published that documented heart block at therapeutic concentrations [ll, 121 and malignant ventricular arrhythmias in the absence of preexisting cardiac disease [13, 141. Prolonged PR, QRS, and QT, intervals and ST-T wave changes primarily associated with overdose became common knowledge [15-191, and some reports suggested that CyAD were likely to induce VPDs [18-201. 392
It has become clear in the last decade that most cyclic antidepressants are Class I antiarrhythmic drugs of considerable potency. Imipramine, in common with quinidine and related Class I antiarrhythmic drugs, has been shown to inhibit the initial inward Na’ current mediated by fast sodium channels [21, 221. The conduction-slowing effects of the tricyclic antidepressants appears to be primarily at the distal HV level as determined by His bundle electrophysiologic studies [20]. The first report that imipramine could be antiarrhythmic in humans, published in 1977, documented suppression of VPDs in two patients being treated for depression [23]. A subsequent prospective study involving 44 subjects revealed greater than 90% suppression of VPDs in 10 of 11 patients who had more than 10 VPDs/hour prior to therapy with imipramine [24]. This study also demonstrated highly significant prolongations of PR, QRS, and QT, intervals, increased heart rate, and lowered T wave amplitude at therapeutic drug levels (100-302 ng/ml). No patients developed high-grade conduction defects. These initial reports have since been supported by further studies [25,26]. More recently, studies have also documented the efficacy of nortriptyline in patients with VPDs [27]. Imipramine has even been used as an experimental antiarrhythmic in ventricular tachycardia [28].
Patients at Risk Since drugs with type I-A antiarrhythmic effects may depress the SA node, the tricyclics can exacerbate the sick sinus syndrome and should not be used prior to pacemaker insertion. There is also a group of patients with subclinical sinus node dysfunction where treatment with Type I antiarrhythmics such as the tricyclics may “unmask” a sick sinus syndrome. For example, there are patients who present with atria1 fachyarrhythmias in whom treatment with cardiac glycosides, beta-adrenergic blocking agents, or type I antiarrhythmics (such as quinidine and the tricyclics) may cause a clinically relevant bradyarrhythmia to develop [28]. Although rare, patients with normal pretreatment ECGs can develop clinically significant forms of AV block when they are given CyAD. For example, Roose et al. found in 150 patients with normal pretreatment ECGs who were treated with either nortriptyline or imipramine, one subject who developed 2:l AV block after treatment [29]. In 24 patients with pretreatment interventricular con-
Antidepressants and Cardiac Disease
duction delays (IVCD) (defined in this study as a QRS interval greater than 0.11 second, upper limit of normal 0.10 seconds) studied by the same investigators, two developed 2:l AV block (9%). Other complications of tricyclics noted in the 24 patients with preexisting IVCD included increases in the QRS interval requiring discontinuation of the drug (two patients), sinus arrest (one patient), and myocardial infarction (one patient). In contrast, in eleven (11) patients with preexisting, first-degree AV block alone, none developed 2:l AV block after tricyclic treatment. It is difficult to predict which patients with relatively benign conduction delays will develop more serious forms of heart block with CyAD treatment. Isolated LBBB, RBBB, or hemiblocks do not necessarily lead to second- or third-degree block with tricyclic treatment. Patients with more extensive conduction disease, such as bifascicular and trifascicular blocks, however, are much more likely to develop second- and third-degree block, since the presence of these abnormalities indicate the presence of more extensive cardiovascular disease. If second- or third-degree heart block is present prior to treatment, CyAD with quinidinelike effects are contraindicated unless a pacemaker is implanted first. As noted earlier, the presence of a widened QRS complex outside the normal range (greater than 0.11 second) apparently raises the relative risk of subsequent conduction abnormalities with tricyclic treatment. Hence, if treatment with a cyclic antidepressant is considered, these patients should be monitored more conservatively with treatment, usually beginning as an inpatient. In patients with first-degree block, tricyclic antidepressants are not contraindicated. Although these patients are theoretically at higher risk for developing higher degrees of AV block, Roose et al. found that in their series of patients with preexisting first-degree AV block, none went on to develop higher grades of block after CyAD treatment [29]. However, if tricyclics are added to other type I antiarrhythmics, additive effects on conduction delay can theoretically occur, and the risk of AV block is increased, although we are not aware of any published reports documenting this interaction causing clinical difficulties. While first-degree heart block, uncomplicated right-bundle block, left-bundle, and focal hemiblocks do not necessarily contraindicate cyclic antidepressant treatment, the same defects should contraindicate CyAD if they have produced syncopal episodes suggestive of Stokes-Adams at-
tacks. In patients with other types of heart block, such as AV junctional nodal and bifascicular and trifascicular blocks, tricyclics are relatively contraindicated in absence of a pacemaker. Patients with sick sinus syndrome will usually already have had pacemakers inserted, after which treatment with CyAD is permissible. Readers are referred to standard textbooks of medicine and cardiology for specific descriptions and pathophysiology of these conduction abnormalities [5, 71. In patients with a history of myocardial infarction uncomplicated by arrhythmias, heart block, unstable angina, or unstable congestive heart failure, antidepressants may be used safely, but there are no data available regarding the optimal timing of initiating treatment in the post-MI period. There are no empiric studies that have reported increased mortality or increased ventricular arrhythmias in patients treated with tricyclics following MI. However, patients with persistently prolonged QT, intervals following MI are at relatively higher risk for subsequent fatal ventricular fibrillation, so tricyclics, which may prolong the QT, interval even further, are contraindicated. Prolonged QT, Torsade de Pointes Syndrome, and WPW Syndrome Even though cyclic antidepressants are safe in most medically ill patients, a few specific groups are at risk for malignant ventricular arrhythmias as a complication of CyAD treatment. Patients with congenital long QT syndrome and patients who have developed significant QT interval prolongation during antidepressant treatment (acquired QT syndrome) [30] are at risk for ventricular tachycardia if the QT interval is further prolonged by CyAD. Lengthening of the QT interval by a cyclic antidepressant is particularly risky if the QT interval, corrected for rate (QT,), is longer than 0.440 seconds [31]. Fortunately, life-threatening QT prolongation by CyAD has been observed primarily in overdose situations [32]. Torsade de Pointes, also called polymorphic ventricular tachycardia, is a very rapid form of ventricular tachycardia that frequently degenerates into ventricular fibrillation. Most patients that develop this arrhythmia have had prolonged QT intervals. Drugs (quinidine, procainamide, disopyramide, phenothiazines, and the tricyclics) are the most common cause of the acquired QT syndrome. Patients with Wolff-Parkinson-White (WPW) 393
A. Stoudemire and I’. Atkinson
syndrome, particularly those that are symptomatic from arrhythmias, deserve evaluation in consultation with a cardiologist before undergoing therapy with CyAD. Most patients with this syndrome are young and present clinically with chief complaints of palpitations and syncope. These patients possess an accessory conduction pathway from the atria to the ventricles, which can lead to fatal arrhythmias. The syndrome is characterized by a short RR interval (%O.lZ set) a widened QRS, and a delta wave (a slowing of the upstroke portion of the QRS complex) in individuals susceptible to episodes of paroxysmal tachycardia. The arrhythmias are believed to derive from the occurrence of “circus movement,” a circular pathway of impulse movement in which the impulse from the normal conduction pathway reenters the atria via the accessory pathway and depolarizes the atria1 myocardium. Patients with WPW syndrome are susceptible to two types of dysrhythmias, ventricular tachycardia and atria1 flutter-fibrillation. If atria1 fibrillation-flutter occurs in WPW patients who have a short refmctory period (CO.27 second) [33], there is an increased risk for re-entrant ventricular tachycardia. Patients with a short refractory period may be identified by a procainamide infusion test, in which the patient is monitored by EKG during intravenous infusion of procainamide [34]. Persistence of a delta wave and shortening of the QRS complex indicate a short refractory period and susceptibility to rapid ventricular arrhythmias when atria1 fibrillation occurs. Although quinidine is a standard treatment for arrhythmias associated with WPW syndrome, drugs with type I-A antiarrhythmic activity have also been observed, during bouts of atria1 flutter-fibrillation, to actually increase the chances of reciprocating tachycardia developing in a subgroup of patients [35]. Quinidinelike drugs may therefore have both positive and negative effects for patients with WPW syndrome. Under certain circumstances, drugs with quinidinelike effects could be problematic [36]. Patients who are identified with WPW syndrome should therefore be started on CyAD only after cardiology consultation has been obtained to evaluate the potential effects of a quinidinelike agent on their vulnerability to arrhythmias.
Cardiology Consultation of Antidepressant
and Choice
The decision to use a cyclic antidepressant in patients with evidence of inter-ventricular conduction 394
delay and/or other evidence of significant conduction disturbances should almost always be made in consultation with a cardiologist. The psychiatrist can facilitate the process of consultation by framing the clinical questions for the cardiology consultant in the most specific manner possible. For example, salient questions to ask would include: a) What would be the effect of the quinidinelike actions of a cyclic antidepressant on this patient cardiac conduction disturbance or other associated arrhythmias? b) Are there any potential hazardous interactions between the quinidinelike action of a cyclic antidepressant and other cardiac drugs the patient may be concurrently using? c) If it is safe to undertake a trial of cyclic antidepressants in this patient, how should the patient be ideally monitored medically in initiating treatment (inpatient, outpatient, with or without continuous EKG monitoring, serial EKGs, etc.)? Framing consultation questions in this manner will enable consultants to readily appreciate the clinical issues at hand and help focus their diagnostic assessment of the patient. After evaluation of the cardiac conduction system has been made, and assuming the patient has been cleared for a trial of CyAD by the cardiology consultant, consideration should be given to the choice of cyclic antidepressant. Limited data are available to provide definitive guidelines for choosing one CyAD over another in the presence of cardiac conduction disorders; all CyAD must be considered to potentially exacerbate cardiac conduction abnormalities. Previously, several reports suggested that doxepin might be a safer CyAD for cardiac patients; an example is a recent study by Ahles et al. [37], who found that the QRS interval was prolonged by maprotiline but appeared to be decreased by doxepin. In this report, however, inadequate information was supplied regarding oral doses and serum levels of the antidepressants studied to firmly document this finding. In an earlier study by Veith [38] of 25 depressed patients with cardiovascular disease treated with imipramine, doxepin or placebo, VPDs were markedly reduced by imipramine, but actually appeared to be increased by doxepin, suggesting a weaker quinidinelike effect of the latter drug. Although the differences in VPD suppression appeared clinically significant, they did not reach statistical significance. Doxepin’s relative superiority in terms of its effect on conduction is therefore largely unsubstantiated. The reports of doxepin’s superior safety margin in
Antidepressantsand Cardiac Disease because doxepin blood levels were probably subtherapeutic [39, 401. Trazodone, a second-generation CyAD, was introduced in the United States in 1982 and was initially received with optimism because of its lack of anticholinergic effects and an apparent absence of quinidinelike prolongation of conduction time in animal studies and in human overdoses. Trazodone has nevertheless been identified in a number of reports as inducing complete heart block, aggravating ventricular arrhythmias, and leading to the development of first-degree heart block even in patients with no prior cardiac history [41-441. One must assume therefore, that any currently available CyAD (including newer agents such as trazodone, maprotiline, and fluoxetine) may be capable of inducing heart block and that this potential side effect be taken into account in every situation. While patients with cardiac conduction disorder are at relatively high risk for complications when treated with CyAD, in many instances these risks can be managed. Each individual case should be evaluated based on a) the benefit and relative risk associated with treatment (risk-benefit ratio), and b) the feasibility of alternative treatments. As noted earlier, certain patients with relatively uncomplicated isolated left-bundle-branch block or hemiblock without evidence of second- or thirddegree heart block can be considered for treatment with CyAD. If it is undertaken, it should usually be done in an inpatient setting after cardiology clearance and with ongoing cardiology consultation. Doses of the CyAD should be titrated upward carefully with serial EKGs done at least on an alternate day basis. Since many arrhythmias are intermittent and may be missed by sporadic testing, 24-hour ambulatory (Holter) monitoring should also be considered. Since the degree of lengthening of cardiac conduction is usually a dose-dependent effect, the quinidinelike effect may be titrated upward by conservative dosing (increases of 10 mg/ day or 25 mg/every third or fourth day) in conjunction with monitoring of EKG parameters and tricyclic serum levels. It may take at least 7 days to reach a steady state serum level with a given dose of antidepressant; correlation of the EKG with drug levelslis most meaningful after a steady state has been achieved. In patients with AV junctional, bifascicular, or trifascicular block, and in patients who have a history of second- or third-degree block, CyAD should be administered only after permanent pacemaker insertion. Pacemaker insertion will largely resolve
concerns about CyAD induced arrhythmias. If pacemaker placement is optional, and is only being considered for reasons of protection against CyADinduced arrhythmias, then alternatives to CyAD usually should be considered first. As noted earlier, there is no clear choice in respect to choosing one CyAD over another in terms of safety for use in patients with conduction disease. Although trazodone appears to be devoid of quinidinelike effects in experimental conditions and even in toxic overdoses, it has nevertheless been noted to cause heart block as an idiosyncratic side-effect. If trazodone is selected, then the same precautions in higher-risk patients should be taken. Even after patients have been safely loaded with CyAD, their EKGs and serum CyAD levels should be periodically monitored on an outpatient basis. There are no systematic data available to dictate with what frequency repeat EKGs should be obtained, but in general a repeat test would be indicated following any significant changes in the patient’s medication regimen, physical symptoms or medical status. Since cardiovascular disease is usually progressive, any increase in the severity of the underlying disease will place the patient at higher risk for conduction abnormalities in the presence of CyAD. Alternatives to psychopharmacologic treatment of depression with cyclic antidepressants include MAO inhibitors, alprazolam, and ECT. MAO inhibitors have negligible effects on the EKG, though one report found that the QT, interval was shortened [45]. There are, however, insufficient data available to fully assess their potential effects on patients with severe cardiovascular disease and conduction abnormalities. MAO inhibitors can cause cardiovascular problems primarily by producing orthostatic hypotension [46]. Alprazolam, in doses of 2-4 mg, has been found to have antidepressant effects [47, 481. The drug, however, is not specifically approved by the FDA for treatment of depression, and problems with dependency and withdrawal remain a major concern. Finally, treatment with electroconvulsive therapy may be used safely in patients with conduction abnormalities and also in patients with pacemakers. In patients with rate-dependent conduction delays who are treated with electroconvulsive therapy, the risk is primarily with the autonomic changes associated with seizure activity such as transient tachycardia and hypertension; these effects can be attenuated with appropriate
A. Stoudemire and P. Atkinson
pharmacologic management prior to and during ECT in high risk patients [49-511. The authors thank Dr. Joel Felner and Dr. Paul Robinson, Department of Medicine ~Cardiology), Emory University School of Medicine, for rezkwing the manuscript.
References 1. Kuhn R: The treatment of depressive states with G22355 (imipramine hydrochloride). Am J Psychiatry 115:459-464, 1958 2. Glassman AH: Cardiovascular effects of tricyclic antidepressants. In JM Davis, JW Maas (eds): The Affective Disorders. Washington DC, American Psychiatric Press, 1983, pp 283-298 3. Guyton AC: Textbook of Medical Physiology, 6th ed. Philadelphia, WB Saunders Co., 1981, pp 165-175 4. Rosen KM, Swiryn SS: Bradyarrhythmia-sinus node dysfunction and conduction defects. In Petersdorf RG, Adams RD, Braunwald E, et al. (eds): Harrison’s Principles of Internal Medicine, 10th ed. New York, McGraw-Hill, 1983, pp 1364-1372 5. Myerburg RJ: Electrocardiography. In Petersdorf RG, Adams RD, Braunwald E, et al. (eds): Harrison’s Principles of Internal Medicine, 10th ed. New York, McGraw-Hill, 1983, p 1322 6. Bigger JT, Hoffman BF: Antiarrhythmic drugs. In Gilman AG, Goodman LS, Rail TW et al. (eds): The Pharmacological Basis of Therapeutics, 7th ed., New York, MacMillan, 1985, pp 748-783 7. Marriot HJL, Meyerburg RJ: Recognition of arrhythmias and conduction abnormalities. In Hurst JW (ed): The Heart, 6th ed. St. Louis, McGraw-Hill Book Co., 1986, pp 461-475 8. Vaughan Williams EM: The classification of antiarrhythmic drugs; In Sandoe E, Flensted-Jensen F, Oleson KH (eds): Symposium on Cardiac Arrhythmias. Sodertalje, Sweden, AB Astra, 1970, p 449 9. Abramowicz M (ed): Drugs for cardiac arrhythmias. Med Let Drugs Ther 28:111-116, 1986 10. Baldessarini RJ: Drugs and the treatment of psychiatric disorders: In Gilman AG, Goodman LS, Rall TW, Murad F (eds): Goodman and Gilman’s The Pharmacologic Basis of Therapeutics, 7th ed. New York, MacMillan Publishing Co., 1985, pp 413-445 11. Smith RB, Rusbatch BJ: Amitriptyline and heart block. Br Med J 3:311, 1967 12. Kantor SJ, Bigger JT, Glassman AH, Macken DL, Perel JM: Imipramine-induced heart block: a longitudinal case study. JAMA 231:1364-1366, 1975 13. Fowler NO, McCall D, Chou TC, et al.: Electrocardiographic changes and cardiac arrhythmias in patients receiving psychotropic drugs. Am J Cardiol 37:223-230, 1976 14. Krikler DM, Curry POL: Torsades de pointes, an atypical ventricular tachycardia. Br Heart J 38:117120, 1976 15. Spiker DC, Weiss AN, Chang SS: Tricyclic antidepressant overdose: Clinical presentation and plasma levels. Clin Pharmacol Ther 18:539-546, 1975
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16. Thorstrand C: Cardiovascular effects of poisoning with tricyclic antidepressants. Acta Med Stand 195505-514, 1974 17. Harthorne JW, Marcus AM, Kaye M: Management of massive imipramine overdose with mannitol and artificial dialysis. N Engl J Med 268:33-36, 1963 18. Mann AM, Catterson AG, MacPherson AS: Toxicity of imipramine: Reports on serious side effects and massive overdosage. Can Med Assoc J 81:23-28,1959 19. Davies B, Burrows G, Dumovic P, Vohra J, Hunt D, Sloman G, Scoggins B: Effects on the heart of different ticyclic antidepressants pp. 54-58. In: Mendels J (ed.) Sinequan (doxepin HCl). Amsterdam, Excerpta Medica, 1975 20. Vohra J, Burrows G, Hunt D, Solman G: The effect of toxic and therapeutic doses of tricyclic antidepressant drugs on intracardiac conduction. Eur J Cardiol 3:219-227, 1975 21. Weld FM, Bigger JT: Electrophysiological effects of imipramine on ovine cardiac Purkinje and ventricular muscle fibers. Circ Res 46:167-175, 1980 22. Rawling D, Fozzard HA: Electrophysiological effects of imipramine on cardiac Purkinje fibers. Am J Cardiol41:387, 1978 23. Bigger JT, Giardina EGV, Perel JM, Kantor SJ, Glassman AH: Cardiac antiarrhythmic effect of imipramine hydrochloride. N Engl J Med 296:206-208,1977 24. Giardina EGV, Bigger JT, Glassman AH, Perel JM, Kantor SJ: The electrocardiographic and antiarrhythmic effects of imipramine hydrochloride at therapeutic plasma concentrations. Circulation 60:1045-1052, 1979 25. Glassman AH, Bigger JT: Cardiovascular effects of therapeutic doses of tricyclic antidepressants. A review. Arch Gen Psychiatry 38:815-820, 1981 26. Veith RC, Raskind MA, Caldwell JH, et al.: Cardiovascular effects of tricyclic antidepressants in depressed patients with chronic heart disease. N Engl J Med 306:954-959, 1982 27. Giardina EV, Barnard T, Johnson L, et al.: The antiarrhythmic effect of nortriptyline in cardiac patients with ventricular premature depolarizations. J Am Cardiol7:1363-1369, 1986 28. Connolly SJ, Mitchell LB, Swerdlow CD, et al.: Clinical efficacy and electrophysiology of imipramine for ventricular tachycardia. J Am Co11 Cardiol 53:516521, 1984 29. Roose SP, Glassman AH, Giardina EGV, et al.: Tricyclic antidepressants in depressed patients with cardiac conduction disease. Arch Gen Psychiatry 44:273-275, 1987 30. Flugelman MY, Tal A, Pollack S, et al.: Psychotropic drugs and long QT syndromes: Case reports. J Clin Psychiatry 46:290-291, 1985 31. Schwartz I’, Wolf S: QT interval prolongation as predictor of sudden death in patients with myocardial infarction. Circulation 5731074-1077, 1978 32. Fricchione GL, Vlay SC: Psychiatric aspects of patients with malignant ventricular arrhythmias. Am J Psychiatry 143:151&1526, 1986 33. Wellens HJ, Durrer D: Wolff-Parkinson-White syndrome and atria1 fibrillation. Relation between refractory period of accessory pathway and ventricular
Antidepressants and Cardiac Disease
34.
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rate during atria1 fibrillation. Am J Cardiol 34:777782, 1974 Wellens JHH, Braat S, Brugada I’, Gorgels APM, Bar FW: Use of procainamide in patients with the WolffParkinson-White syndrome to disclose a short refractory period of the accessory pathway. Am J Cardiol50:1087-1089, 1982 Sellers TD, Campbell RWF, Bashore TM, et al.: Effects of procainamide and quinidine sulfate in the Circulation Wolff-Parkinson-White Syndrome. 55:15-22, 1977 Vieweg WVR, Hillard JR, Hoffman MA, et al.: Depression and the Wolff-Parkinson-White Syndrome. Psychosomatics 29:113-116, 1988 Ahles S, Swirtsman H, Halaris A, et al.: Comparative cardiac effects of maprotiline and doxepin in elderly depressed patients. J Clin Psychiatry 45:460-465, 1984 Veith RC, Raskind MA, Caldwell JH, et al.: Cardiovascular effects of tricyclic antidepressants in depressed patients with chronic heart disease. N Eng J Med 306:954-959, 1982 Luchins DJ: Review of clinical and animal studies comparing the cardiovascular effects of doxepin and other tricyclic antidepressants. Am J Psychiatry 140:1006-1009, 1983 Burrows CD, Vohra J, Dumovic P, et al.: TCA drugs in cardiac conduction. Prog Neuropsychopharmacol Biol Psychiatry 1:329-334, 1977 Rausch JL, Pavlinac DM, Newman PE: Complete heart block following a single dose of trazodone. Am J Psychiatry 141:1472-1473, 1984
42. Janowsky D, Curtis G, Zisook S, et al.: Ventricular arrhythmias possibly aggravated by trazodone. Am J Psychiatry 140:796-797, 1983 43. Irwin M, Spar JE: Reversible cardiac conduction abnormality associated with trazodone administration (letter). Am J Psychiatry 140:945-946, 1983 44. Coccaro EF, Siever LJ: Second generation antidepressants: A comparative review. J Clin Pharmacol 25:241-260, 1985 45. Robinson DS, Nies A, Corcella J, et al.: Cardiovascular effects of phenelzine and amitriptyline in depressed outpatients, J Clin Psychiatry 43:8-15, 1982 46. Cassem N: Cardiovascular effects of antidepressants. J Clin Psychiatry 43:22-28, 1982 47. Feighner JP, Aden CC, Fabre LF, et al.: Comparison of alprazolam, imipramine, and placebo in the treatment of depression. JAMA 249:3057-3064, 1983 48. Rickels K, Feighner Jr, Smith WT: Alprazolam, amitriptyline, doxepin, and placebo in the treatment of depression. Arch Gen Psychiatry 42:134-141, 1985 49. Stoudemire A, Fogel 8: Psychopharmacology in the medically ill. In Stoudemire A, Fogel B (eds): Principles of Medical Psychiatry. Orlando, Fla., &me & Stratton, 1987, pp. 79-112 50. Weiner RD, Coffey CE: Electroconvulsive therapy in the medically ill. In Stoudemire A, Fogel B (eds): Principles of Medical Psychiatry. Orlando, Fla., Grune & Stratton, 1987, pp. 113-134 51. Cohen-Cole SA, Stoudemire A: Major depression and physical illness: Special considerations in diag-. nosis and biological treatment. Psych Clin North Am lO:l-17, 1987
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Use of Cyclic Antidepressants in Patients with Cardiac Conduction Disturbances Alan Stoudemire,
M.D., and Prescott Atkinson,
M.D., Ph.D.
Abstract: Cyclic antidepressants can produce cardiac complications in patients with certain types of cardiac conduction abnormalities. Most cyclic antidepressants have a quinidinelike effect on the heart, which, in combination with Type 1 antiarrhythmic agents such as quinidine, disopyramide and procainamide, may induce heart &lock and potentially lethal arrhythmias in suscepfible individuals. Patients with known cardiovascular disease warrant careful evaluation beforetricyclic therapy is initiated. Guidelines are presented for identifying high-risk patients and for using cyclic antidepressants in patients with cardiac conduction abnormalities.
channels. On account of this effect, CyAD can exhibit significant quinidinelike properties on cardiac conduction and may have additive effects with Type I antiarrhythmic drugs [2I. In medically ill patients with heart disease, the possible effects of CyAD on the heart and interactions with cardiac medications should be considered prior to initiation of therapy. This discussion will focus on quinidinelike effects of CyAD and offer guidelines for the assessment and treatment of depressed patients with cardiac conduction abnormalities.
Since the initial finding by Kuhn in i958 [l] that imipramine improved endogenous depression, the class of drugs known as the tricyclic, tetracyclic, and heterocyclic antidepressants (collectively referred to here as the cyclic antidepressants or CyAD) have become the first-line drug treatment of major depression. In addition to inhibiting presynaptic neuronal reuptake of biogenic amines such as norepinephrine and serotonin, these agents also inhibit transmembrane fast sodium
Normal and Abnormal Cardiac Conduction
We are very pleased to initiate the new section on clinical problems in psychiatric treatment of the medically ill with the paper by Dr. Stoudemire and Dr. Atkinson on the use of cyclic with cardiac antidepressants in patients conduction disturbances. From the Medical Psychiatry Unit, Emory University Hospital and Emory University School of Medicine, Atlanta, Georgia.
General Hospitd Psychiaty 10,389-397, 1988 0 1988 Elsevier Science Publishing Co., Inc.
655 Avenue of the Americas, New York, NY 10010
Under normal conditions, the heartbeat originates in the sinoatrial (SA) node, which is located at the junction of the superior vena cava and the right atrium (Fig. 1) [3]. Impulses originating in this dominant pacemaker spread out and depolarize both atria and reach the atrioventricular (AV) node. Except for the conduction pathway extending from the AV node, located in the right posterior portion of the interatrial septum, the atria and ventricles are electrically isolated from each other by fibrous tissue. The pathway from the AV node is called the bundle of His and extends to the top of the interventricular septum, where it gives rise to the left- and right-bundle branches. The left-bundle
389 ISSN 0163~&P&3/88/$3.50
A.
Stoudemire and I’. Atkinson
-66 RBB
Figure 1. Cardiac conduction system (see text). SAN, sinoatrialnode; AVIV, Atrioventricular node; BH, Bundle of His; LBB, Left bundle branch; and RBB, Right bundle branch; (Adapted from Glassman AH, Bigger JT: Cardiovascular effects of therapeutic doses of tricyclic antidepressants. Arch Gen Psychiatry 38:815-820, 1981.)
branch in turn divides to form the left-anterior and left-posterior fascicles. The right-bundle branch and left fascicles continue subendocardially down the length of the interventricular septum and give rise to the Purkinje fibers of the ventricles, which fan out and rapidly conduct the impulse across the ventricular myocardium. On the electrocardiogram, the interval between the P wave and the QRS complex is the PR interval. The PR interval is measured from the onset of atria1 depolarization (P) to the onset of ventricular depolarization (Q). Its normal duration in adults is 0.12-0.20 seconds. The PR interval is used as a measure of AV conduction time. The PR interval may be subdivided by His bundle electrocardiography into the PA interval (a measure of intraatrial conduction time), AH interval (a measure of AV nodal conduction time), and HV interval (a measure of His-Purkinje conduction time) [4]. The QRS complex (normally 0.04-0.10 seconds) represents the time of ventricular muscle depolarization. The QRS can be prolonged by blocks in the bundle branches, the Purkinje system, or in the myocardium itself. Clinically, bundle branch blocks are particularly common and important. The QT interval is a rough approximation of the refractory
period of the ventricles and is measured from the beginning of the QRS complex to the end of the T wave. The QT interval is rate dependent, and when corrected for rate, is designated the “QT,” interval 151. Cardiac arrhythmias can be due either to abnormalities of impulse generation or to abnormalities of impulse conduction [5]. Many defects involve either abnormalities in the generation of impulses in the SA node or in the conduction pathways to the ventricles [7]. Late emergence or absence of impulses from the SA node is termed SA block. The sick sinus (bradycardia-tachycardia) syndrome refers to sinus node dysfunction, which results in symptomatic bradyarrhythmia, including sinus bradycardia, SA block, or sinus arrest [4]. Atria1 tachyarrhythmias observed in this syndrome include paroxysmal atria1 fibrillation, paroxysmal atria1 flutter, and paroxysmal atria1 tachycardia. If AV conduction is consistent, but the AV conduction time is excessive, first degree AV block is present. First-degree AV block is defined as a prolonged PR interval (greater than 0.20 seconds in adults) with AV conduction intact; P waves are normal, and a QRS complex follows every P wave. Second-degree AV block is a form of AV block with blocked P waves, i.e., P waves that are not transmitted and, therefore, are not followed by a QRS complex. Second-degree AV block can be divided into the relatively benign Mobitz type I (Wenckebach), and the much more ominous Mobitz type II. Mobitz type I (Wenckebach) second-degree block is characterized by progressive lengthening of the PR interval prior to the blocked P wave. Mobitz type II second degree blockis characterized by fixed PR intervals prior to the blocked P wave. Third-degree (complete) heart block is defined by a total lack of conduction between the atria and the ventricles. Third-degree heart block results in complete AV dissociation, with the atial rate usually faster than the ventricular rate. Table 1 summarizes the three degrees of AV block. Defects in the conduction of impulses downstream from the AV node give rise to the various bundle branch blocks (left-bundle branch block, right-bundle branch blocks, and hemiblocks), which announce their presence by characteristic changes in the ECG [4]. Total interruption of conduction can occur at the AV node, the Bundle of His, or within branches of the trifascicular conduction system.
Antidepressants and Cardiac Disease
Table 1. Salient Features
of A-V Block Features
Degree First degree
Prolongation of PR interval beyond 0.20 set Dropped ventricular responses Progressive lengthening of PR intervals until a beat is dropped (Wenckebach phenomenon)
Second degree Type I
Consecutively conducted beats with constant PR intervals before the dropped beat
Type II High-grade or advanced Third degree
Two or more consecutively dropped beats (at norma atria1 rates) Complete AV block: No conducted beats in the presence of a slow ventricular rhythm
(under 45) and ample opportunity for conduction Reproduced with permission from Practical Electrocardiography, by HJL Marriott, The Williams & Wilkins Co., Baltimore, 1972. +50
Table 2. Cardiac Effects of Selected
Antiarrhythmic
Drugs [6, 91 EKG Effects QRS QT,
--FAST
r
Heart block
DW?
PR
Quinidine Disopyramide (Norpace) Procainamide (Pronestyl) Tricyclic Antidepressants
+ + + +
+ 2 + +
+ + + +
+ ? + +
0
0
0
0
+
+
*
+
+ +
0 0
-
+ +
+ +
+ 0
+ +
+ *
+ +
0 0
0 0
+ +
Class I-A
Class I-B Lidocaine (Xylocaine) Class I-C Flecainide (Tambocor) Class II Propranolol (Inderal) Acebutolol (Se&al) Class III Amiodarone (Cordarone) Bretylium (Bretylol) Class IV Verapamil (Isoptin, Calan) Diltiazem (Cardizem)
\ \
Effects listed as “+” are increased or present, as “-I’ are decreased, as “ 2 ” are increased or unchanged (variable), and as “0” are unchanged.
Antiarrhythmic
\” \
Agents and CyAD
Four classes of antiarrhythmic agents have been described, several of which have effects on the heart similar to those of the cyclic antidepressants (Table 2) [6, 8, 91. The first of these, class I agents, e.g., quinidine, lidocaine, and flecainide, depress the fast Na’ channel, which mediates phase 0 of the action potential, the initial rapid depolarization (Fig. 2). Class I drugs have been further subdivided into subclasses A, B, or C depending on their differential effects on fast sodium channels and re-
I
250 TIME (msec)
\c
500
Figure 2. Effects of quinidinelike drugs on the cardiac action potential. Dotted line represents normal action potential, and solid line represents effects on the action potential of quinidinelike agents in slowing the response. Phase “0” is depolarization and rapid reversal of transmembrane potential. In most cardiac cells, phase 0 is generated by the influx of Na’ ions through selected transmembrane channels. Phase 1, 2, and 3 represent repolarization. Phase 4 is the diastolic phase. The Ca‘ + or slow channel is activated during the plateau phase, which allows secondary inward current to flow. These drugs reduce the slope of phase 4 (tending to eliminate ectopic foci), slow the rate of fast depolarization (phase 0), and thus retard impulse conduction and extend the refractory period. (Adapted in part from Bigger JT, Hoffman BF: Antiarrhythmic drugs, In Gilman A, Goodman LS, Rall TW, Murad F (eds): The Pharmacological Basis of Therapeutics, 7th ed. New York, MacMillan Publishing Company, 1985, ch. 31, p. 749.) polarization. Class I-A drugs (quinidine, procainamide, disopyramide, and tricyclic antidepressants) not only depress fast Na* channels, but also prolong repolarization. Class I-B drugs (e.g., lidocaine, phenytoin, tocainide, mexiletine) have minimal phase-O depression and shorten repolarization. Class I-C drugs (e.g., flecainide) depress 391
A. Stoudemire
and P. Atkinson
but have little effect on depolarization, repolarization. Class II antiarrhythmics, e.g., propranolol and acebutolol, work primarily by antagonizing the effects of catecholamines on cardiac beta-adrenergic receptors. Class III antiarrhythmic agents such as amiodarone increase the duration of action potential via sodium channel blockage during phase 2 and part of phase 3 of the action potential. Class IV drugs are calcium channel blockers, (e.g. verapamil, diltiazem), which delay repolarization by inhibiting the slow inward Ca’ +-mediated current. Class IV antiarrhythmics lead to prolongation of the plateau phase (phase II) of the action potential. Some calcium-entry-blocking agents such as diltiazem and verapamil can adversely affect AV nodal function. Because they depress myocardial impulse conduction, drugs with quinidine-like antiarrhythmic activity (e.g., tricyclic antidepressants) affect various ECG parameters [lo]. They often increase the length of the PR, QRS, and QT, segments. Perhaps their most significant effect is the lengthening of the ratio of the effective refractory period (ERP) over the action potential of myocardial fibers; this effect serves to suppress ectopic pacemaker foci that can give rise to atria1 flutter, atria1 fibrillation, ventricular tachycardia, and ventricular premature depolarizations (VPD). These drugs also often cause a rise in heart rate partly because of direct anticholinergic (vagolytic) effects and partly from reflex sympathetic activity induced by their hypotensive a,-antagonist effects. The combined effects of slowed impulse conduction, decreased automaticity, and lengthening of the ERWaction potential ratio in suppressing arrhythmias are complex, and the relative importance of each is not yet fully understood.
Cyclic Antidepressants and Cardiac Conduction In the years since their initial use as antidepressants, CyAD gained anecdotal notoriety for untoward effects upon the heart. There were case reports published that documented heart block at therapeutic concentrations [ll, 121 and malignant ventricular arrhythmias in the absence of preexisting cardiac disease [13, 141. Prolonged PR, QRS, and QT, intervals and ST-T wave changes primarily associated with overdose became common knowledge [15-191, and some reports suggested that CyAD were likely to induce VPDs [18-201. 392
It has become clear in the last decade that most cyclic antidepressants are Class I antiarrhythmic drugs of considerable potency. Imipramine, in common with quinidine and related Class I antiarrhythmic drugs, has been shown to inhibit the initial inward Na’ current mediated by fast sodium channels [21, 221. The conduction-slowing effects of the tricyclic antidepressants appears to be primarily at the distal HV level as determined by His bundle electrophysiologic studies [20]. The first report that imipramine could be antiarrhythmic in humans, published in 1977, documented suppression of VPDs in two patients being treated for depression [23]. A subsequent prospective study involving 44 subjects revealed greater than 90% suppression of VPDs in 10 of 11 patients who had more than 10 VPDs/hour prior to therapy with imipramine [24]. This study also demonstrated highly significant prolongations of PR, QRS, and QT, intervals, increased heart rate, and lowered T wave amplitude at therapeutic drug levels (100-302 ng/ml). No patients developed high-grade conduction defects. These initial reports have since been supported by further studies [25,26]. More recently, studies have also documented the efficacy of nortriptyline in patients with VPDs [27]. Imipramine has even been used as an experimental antiarrhythmic in ventricular tachycardia [28].
Patients at Risk Since drugs with type I-A antiarrhythmic effects may depress the SA node, the tricyclics can exacerbate the sick sinus syndrome and should not be used prior to pacemaker insertion. There is also a group of patients with subclinical sinus node dysfunction where treatment with Type I antiarrhythmics such as the tricyclics may “unmask” a sick sinus syndrome. For example, there are patients who present with atria1 fachyarrhythmias in whom treatment with cardiac glycosides, beta-adrenergic blocking agents, or type I antiarrhythmics (such as quinidine and the tricyclics) may cause a clinically relevant bradyarrhythmia to develop [28]. Although rare, patients with normal pretreatment ECGs can develop clinically significant forms of AV block when they are given CyAD. For example, Roose et al. found in 150 patients with normal pretreatment ECGs who were treated with either nortriptyline or imipramine, one subject who developed 2:l AV block after treatment [29]. In 24 patients with pretreatment interventricular con-
Antidepressants and Cardiac Disease
duction delays (IVCD) (defined in this study as a QRS interval greater than 0.11 second, upper limit of normal 0.10 seconds) studied by the same investigators, two developed 2:l AV block (9%). Other complications of tricyclics noted in the 24 patients with preexisting IVCD included increases in the QRS interval requiring discontinuation of the drug (two patients), sinus arrest (one patient), and myocardial infarction (one patient). In contrast, in eleven (11) patients with preexisting, first-degree AV block alone, none developed 2:l AV block after tricyclic treatment. It is difficult to predict which patients with relatively benign conduction delays will develop more serious forms of heart block with CyAD treatment. Isolated LBBB, RBBB, or hemiblocks do not necessarily lead to second- or third-degree block with tricyclic treatment. Patients with more extensive conduction disease, such as bifascicular and trifascicular blocks, however, are much more likely to develop second- and third-degree block, since the presence of these abnormalities indicate the presence of more extensive cardiovascular disease. If second- or third-degree heart block is present prior to treatment, CyAD with quinidinelike effects are contraindicated unless a pacemaker is implanted first. As noted earlier, the presence of a widened QRS complex outside the normal range (greater than 0.11 second) apparently raises the relative risk of subsequent conduction abnormalities with tricyclic treatment. Hence, if treatment with a cyclic antidepressant is considered, these patients should be monitored more conservatively with treatment, usually beginning as an inpatient. In patients with first-degree block, tricyclic antidepressants are not contraindicated. Although these patients are theoretically at higher risk for developing higher degrees of AV block, Roose et al. found that in their series of patients with preexisting first-degree AV block, none went on to develop higher grades of block after CyAD treatment [29]. However, if tricyclics are added to other type I antiarrhythmics, additive effects on conduction delay can theoretically occur, and the risk of AV block is increased, although we are not aware of any published reports documenting this interaction causing clinical difficulties. While first-degree heart block, uncomplicated right-bundle block, left-bundle, and focal hemiblocks do not necessarily contraindicate cyclic antidepressant treatment, the same defects should contraindicate CyAD if they have produced syncopal episodes suggestive of Stokes-Adams at-
tacks. In patients with other types of heart block, such as AV junctional nodal and bifascicular and trifascicular blocks, tricyclics are relatively contraindicated in absence of a pacemaker. Patients with sick sinus syndrome will usually already have had pacemakers inserted, after which treatment with CyAD is permissible. Readers are referred to standard textbooks of medicine and cardiology for specific descriptions and pathophysiology of these conduction abnormalities [5, 71. In patients with a history of myocardial infarction uncomplicated by arrhythmias, heart block, unstable angina, or unstable congestive heart failure, antidepressants may be used safely, but there are no data available regarding the optimal timing of initiating treatment in the post-MI period. There are no empiric studies that have reported increased mortality or increased ventricular arrhythmias in patients treated with tricyclics following MI. However, patients with persistently prolonged QT, intervals following MI are at relatively higher risk for subsequent fatal ventricular fibrillation, so tricyclics, which may prolong the QT, interval even further, are contraindicated. Prolonged QT, Torsade de Pointes Syndrome, and WPW Syndrome Even though cyclic antidepressants are safe in most medically ill patients, a few specific groups are at risk for malignant ventricular arrhythmias as a complication of CyAD treatment. Patients with congenital long QT syndrome and patients who have developed significant QT interval prolongation during antidepressant treatment (acquired QT syndrome) [30] are at risk for ventricular tachycardia if the QT interval is further prolonged by CyAD. Lengthening of the QT interval by a cyclic antidepressant is particularly risky if the QT interval, corrected for rate (QT,), is longer than 0.440 seconds [31]. Fortunately, life-threatening QT prolongation by CyAD has been observed primarily in overdose situations [32]. Torsade de Pointes, also called polymorphic ventricular tachycardia, is a very rapid form of ventricular tachycardia that frequently degenerates into ventricular fibrillation. Most patients that develop this arrhythmia have had prolonged QT intervals. Drugs (quinidine, procainamide, disopyramide, phenothiazines, and the tricyclics) are the most common cause of the acquired QT syndrome. Patients with Wolff-Parkinson-White (WPW) 393
A. Stoudemire and I’. Atkinson
syndrome, particularly those that are symptomatic from arrhythmias, deserve evaluation in consultation with a cardiologist before undergoing therapy with CyAD. Most patients with this syndrome are young and present clinically with chief complaints of palpitations and syncope. These patients possess an accessory conduction pathway from the atria to the ventricles, which can lead to fatal arrhythmias. The syndrome is characterized by a short RR interval (%O.lZ set) a widened QRS, and a delta wave (a slowing of the upstroke portion of the QRS complex) in individuals susceptible to episodes of paroxysmal tachycardia. The arrhythmias are believed to derive from the occurrence of “circus movement,” a circular pathway of impulse movement in which the impulse from the normal conduction pathway reenters the atria via the accessory pathway and depolarizes the atria1 myocardium. Patients with WPW syndrome are susceptible to two types of dysrhythmias, ventricular tachycardia and atria1 flutter-fibrillation. If atria1 fibrillation-flutter occurs in WPW patients who have a short refmctory period (CO.27 second) [33], there is an increased risk for re-entrant ventricular tachycardia. Patients with a short refractory period may be identified by a procainamide infusion test, in which the patient is monitored by EKG during intravenous infusion of procainamide [34]. Persistence of a delta wave and shortening of the QRS complex indicate a short refractory period and susceptibility to rapid ventricular arrhythmias when atria1 fibrillation occurs. Although quinidine is a standard treatment for arrhythmias associated with WPW syndrome, drugs with type I-A antiarrhythmic activity have also been observed, during bouts of atria1 flutter-fibrillation, to actually increase the chances of reciprocating tachycardia developing in a subgroup of patients [35]. Quinidinelike drugs may therefore have both positive and negative effects for patients with WPW syndrome. Under certain circumstances, drugs with quinidinelike effects could be problematic [36]. Patients who are identified with WPW syndrome should therefore be started on CyAD only after cardiology consultation has been obtained to evaluate the potential effects of a quinidinelike agent on their vulnerability to arrhythmias.
Cardiology Consultation of Antidepressant
and Choice
The decision to use a cyclic antidepressant in patients with evidence of inter-ventricular conduction 394
delay and/or other evidence of significant conduction disturbances should almost always be made in consultation with a cardiologist. The psychiatrist can facilitate the process of consultation by framing the clinical questions for the cardiology consultant in the most specific manner possible. For example, salient questions to ask would include: a) What would be the effect of the quinidinelike actions of a cyclic antidepressant on this patient cardiac conduction disturbance or other associated arrhythmias? b) Are there any potential hazardous interactions between the quinidinelike action of a cyclic antidepressant and other cardiac drugs the patient may be concurrently using? c) If it is safe to undertake a trial of cyclic antidepressants in this patient, how should the patient be ideally monitored medically in initiating treatment (inpatient, outpatient, with or without continuous EKG monitoring, serial EKGs, etc.)? Framing consultation questions in this manner will enable consultants to readily appreciate the clinical issues at hand and help focus their diagnostic assessment of the patient. After evaluation of the cardiac conduction system has been made, and assuming the patient has been cleared for a trial of CyAD by the cardiology consultant, consideration should be given to the choice of cyclic antidepressant. Limited data are available to provide definitive guidelines for choosing one CyAD over another in the presence of cardiac conduction disorders; all CyAD must be considered to potentially exacerbate cardiac conduction abnormalities. Previously, several reports suggested that doxepin might be a safer CyAD for cardiac patients; an example is a recent study by Ahles et al. [37], who found that the QRS interval was prolonged by maprotiline but appeared to be decreased by doxepin. In this report, however, inadequate information was supplied regarding oral doses and serum levels of the antidepressants studied to firmly document this finding. In an earlier study by Veith [38] of 25 depressed patients with cardiovascular disease treated with imipramine, doxepin or placebo, VPDs were markedly reduced by imipramine, but actually appeared to be increased by doxepin, suggesting a weaker quinidinelike effect of the latter drug. Although the differences in VPD suppression appeared clinically significant, they did not reach statistical significance. Doxepin’s relative superiority in terms of its effect on conduction is therefore largely unsubstantiated. The reports of doxepin’s superior safety margin in
Antidepressantsand Cardiac Disease because doxepin blood levels were probably subtherapeutic [39, 401. Trazodone, a second-generation CyAD, was introduced in the United States in 1982 and was initially received with optimism because of its lack of anticholinergic effects and an apparent absence of quinidinelike prolongation of conduction time in animal studies and in human overdoses. Trazodone has nevertheless been identified in a number of reports as inducing complete heart block, aggravating ventricular arrhythmias, and leading to the development of first-degree heart block even in patients with no prior cardiac history [41-441. One must assume therefore, that any currently available CyAD (including newer agents such as trazodone, maprotiline, and fluoxetine) may be capable of inducing heart block and that this potential side effect be taken into account in every situation. While patients with cardiac conduction disorder are at relatively high risk for complications when treated with CyAD, in many instances these risks can be managed. Each individual case should be evaluated based on a) the benefit and relative risk associated with treatment (risk-benefit ratio), and b) the feasibility of alternative treatments. As noted earlier, certain patients with relatively uncomplicated isolated left-bundle-branch block or hemiblock without evidence of second- or thirddegree heart block can be considered for treatment with CyAD. If it is undertaken, it should usually be done in an inpatient setting after cardiology clearance and with ongoing cardiology consultation. Doses of the CyAD should be titrated upward carefully with serial EKGs done at least on an alternate day basis. Since many arrhythmias are intermittent and may be missed by sporadic testing, 24-hour ambulatory (Holter) monitoring should also be considered. Since the degree of lengthening of cardiac conduction is usually a dose-dependent effect, the quinidinelike effect may be titrated upward by conservative dosing (increases of 10 mg/ day or 25 mg/every third or fourth day) in conjunction with monitoring of EKG parameters and tricyclic serum levels. It may take at least 7 days to reach a steady state serum level with a given dose of antidepressant; correlation of the EKG with drug levelslis most meaningful after a steady state has been achieved. In patients with AV junctional, bifascicular, or trifascicular block, and in patients who have a history of second- or third-degree block, CyAD should be administered only after permanent pacemaker insertion. Pacemaker insertion will largely resolve
concerns about CyAD induced arrhythmias. If pacemaker placement is optional, and is only being considered for reasons of protection against CyADinduced arrhythmias, then alternatives to CyAD usually should be considered first. As noted earlier, there is no clear choice in respect to choosing one CyAD over another in terms of safety for use in patients with conduction disease. Although trazodone appears to be devoid of quinidinelike effects in experimental conditions and even in toxic overdoses, it has nevertheless been noted to cause heart block as an idiosyncratic side-effect. If trazodone is selected, then the same precautions in higher-risk patients should be taken. Even after patients have been safely loaded with CyAD, their EKGs and serum CyAD levels should be periodically monitored on an outpatient basis. There are no systematic data available to dictate with what frequency repeat EKGs should be obtained, but in general a repeat test would be indicated following any significant changes in the patient’s medication regimen, physical symptoms or medical status. Since cardiovascular disease is usually progressive, any increase in the severity of the underlying disease will place the patient at higher risk for conduction abnormalities in the presence of CyAD. Alternatives to psychopharmacologic treatment of depression with cyclic antidepressants include MAO inhibitors, alprazolam, and ECT. MAO inhibitors have negligible effects on the EKG, though one report found that the QT, interval was shortened [45]. There are, however, insufficient data available to fully assess their potential effects on patients with severe cardiovascular disease and conduction abnormalities. MAO inhibitors can cause cardiovascular problems primarily by producing orthostatic hypotension [46]. Alprazolam, in doses of 2-4 mg, has been found to have antidepressant effects [47, 481. The drug, however, is not specifically approved by the FDA for treatment of depression, and problems with dependency and withdrawal remain a major concern. Finally, treatment with electroconvulsive therapy may be used safely in patients with conduction abnormalities and also in patients with pacemakers. In patients with rate-dependent conduction delays who are treated with electroconvulsive therapy, the risk is primarily with the autonomic changes associated with seizure activity such as transient tachycardia and hypertension; these effects can be attenuated with appropriate
A. Stoudemire and P. Atkinson
pharmacologic management prior to and during ECT in high risk patients [49-511. The authors thank Dr. Joel Felner and Dr. Paul Robinson, Department of Medicine ~Cardiology), Emory University School of Medicine, for rezkwing the manuscript.
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