Original Author: Bruce Alexander, Pharm.D, BCPP
Latest Reviser: Bruce Alexander, Pharm.D, BCPP
Creation Date: 1996
Peer Review Status: Internally Peer Reviewed
TRICYCLIC ANTIDEPRESSANTS
Tricyclic antidepressant (TCA) overdoses often produce serious cardiac effects. Recent prospective, plasma level controlled studies have improved our understanding of the cardiovascular effects of these drugs at therapeutic levels.
Most literature discusses the effects of imipramine, desipramine, amitriptyline, nortriptyline, and doxepin on the cardiovascular system. Little information exits on the effects of trimipramine and protriptyline. That these two drugs produce different effects than the five listed remains to be demonstrated.
VASCULATURE
Orthostatic hypotension has been reported with all TCAs. Relative differences between drugs are now being investigated. The mechanism of TCA-induced orthostasis may be adrenergic blocking effects and may correlate with the relative affinity for alpha-noradrenergic receptors.
Interestingly, 2 recent reports have suggested that pretreatment orthostatic hypotension predicted TCA treatment response (Jarvk et al 1983; Schneider et al 1986). The study drugs included imipramine, doxepin, and nortriptyline. One study found that 85% of those patients who improved had blood pressure fall of at least 12 mm Hg (Schneider et al 1986).
Imipramine
Glassman et al. examined the effects of imipramine on blood pressure in a prospective and retrospective study (Glassman et al 1979). In the prospective study of 44 depressed patients given imipramine in doses to achieve antidepressant plasma concentrations greater than 200 ng/ml there was no effect of the drug on lying blood pressure. When patients stood up, the drug produced an average fall in systolic pressure of 26 mm Hg (p < .001). Contrary to expectation, this fall was independent of patient age, preexisting heart disease, or plasma level of the drug. The best predictor of orthostatic hypotension during treatment was the degree of orthostatic drop in pressure before treatment (r = .70, p <0.001). Orthostatic hypotension was detected in the first week of imipramine treatment and persisted throughout the entire four-week treatment period. In addition, the blood pressure drops were not exacerbated by a single daily dose administered at bedtime.
To establish the clinical significance of this orthostatic drop in pressure, a retrospective study of 148 depressed patients treated with imipramine was conducted. These 148 patients, average age 59 years, received an average dose of imipramine 225 mg/d. Almost 20% of them had symptoms usually associated with orthostatic hypotension that was severe enough to interfere with their treatment. More than 4% sustained physical injuries.
Nortriptyline
Freyschuss et al. studied 40 depressed patients treated with nortriptyline 25 or 50 mgm t.i.d. for three weeks (Freyschuss et al 1970). The following circulatory variables were observed prior to and during drug therapy: heart rate and blood pressure at rest (in supine and standing positions), working capacity, EKG at rest and during exercise on a bicycle ergometer. Diastolic blood pressure in the supine position rose slightly; in the standing position the pretreatment increase in diastolic pressure was abolished.
In contrast, Reed et al reported average plasma nortriptyline levels of 90-160 ng/ml produced a 14.3 mm Hg mean drop in systolic blood pressure when patients changed from a lying to standing position (Reed et al 1980). There was no significant effect on the diastolic component. This effect was independent of age as the degree of orthostatic hypotension did not differ in five geriatric (mean age of 67.8 years, range of 60-78 years) and three younger patients (mean age 25.8 years, range 21-32 years).
Roose et al reported the results of 2 studies comparing the orthostatic effect of imipramine and nortriptyline (Roose et al 1981). Group I consisted of 15 patients receiving nortriptyline, with levels in the therapeutic window (50-150 ng/ml), compared to 44 patients with therapeutic imipramine levels. Both groups were on medication for 3 weeks and were similar in age. Group II was 8 patients treated with both imipramine and nortriptyline. In both Group I and II, patients had at least 1 week of baseline blood pressure measurements before start of the antidepressant. In Group I the pre-drug orthostatic drop was 8 mm Hg for nortriptyline and 11 mm Hg for imipramine. Blood pressures were measured AM and PM. Patients would lie down for 5 mins to obtain a lying BP and BP was taken after standing 1 min. Mean BPs were obtained by pooling the data for each group. Orthostatic drop was defined as the lying systolic blood pressure minus the standing systolic blood pressure.
In Group I, the mean orthostatic drop with imipramine was significantly (p <0.001) greater than that while on nortriptyline (26 vs 13 mm Hg, respectively). In the Group II study imipramine produced a mean orthostatic drop of 33 mm Hg and nortriptyline produced a drop of 22 mm Hg (p <0.01).
The same group in a recent report of patients treated with imipramine, 7% of those with normal ECGs and 32% with cardiac conduction disease developed orthostatic hypotension requiring drug discontinuation (Roose et al 1987a). Among patients treated with nortriptyline, none with normal ECGs and one of 20 (5%) with conduction disease developed postural problems. Therefore, imipramine-induced orthostasis was significantly more common in patients with conduction disturbance (p<0.001) than in similar-aged patients without conduction disease. Nortriptyline caused minimal orthostatic changes compared with imipramine, even in patients with conduction disturbances (p<0/05).
Thayssen et al. contrasted the effects of imipramine and nortriptyline on blood pressure in a geriatric population (62-78 y.o.) (Thayssen et al 1981). Total imipramine levels were adjusted to be greater than 250 ng/ml while nortriptyline levels were between 60 to 150 ng/ml. However it was impossible to reach the therapeutic imipramine levels in most patients because of the severity of the orthostatic blood pressure. Two patients fell and sustained fractures-one after only 3 days of therapy with a total level of 53 ng/ml. The orthostatic change was described as being primarily a change in systolic blood pressure lasting from 2-5 minutes. Unlike Glassman et al. the authors did not find a correlation between pretreatment orthostatic decreases and the treatment orthostatic drops. No significant orthostatic blood pressure change occurred with nortriptyline.
Desipramine
Rudorfer and Young reported on 14 outpatients aged 22 to 41 years old (mean 30 years) who were free of medical illness and receiving desipramine (Rudorfer et al 1980). There was a significant (p < 0.02) decrease in mean systolic blood pressure in a sitting and standing position. A mean pre-treatment change of 11 and a treatment change of 9 mm Hg were observed. Standing and sitting diastolic blood pressures were not significantly affected. All patients received desipramine 150 mg/d and the mean steady-state plasma level was 201 ng/ml, the highest value being 407 ng/ml. They noted the subjects did not have subjective complaints or objective complications of orthostatic hypotension.
Doxepin
Linnoila et al. reported the effects of doxepin 210 ± 85 mg/d vs placebo on blood pressure (Linnoila 1982). Unlike other TCAs, the drug produced a significant mean decrease in lying systolic (14 mm) and diastolic (15 mm) blood pressure. Doxepin, also, decreased the mean standing diastolic (12 mm) and systolic (24 mm) pressures.
Veith et al. found doxepin (25-300 mg/d, mean 153 mg) to produce similar decreases in standing blood pressure as compared to imipramine (10-200 mg/d, mean 130 mg) (Veith et al 1982). A decrease of 6 ± 11 mm Hg in standing systolic blood pressure was observed for both drugs. One patient on imipramine and three patients on doxepin had postural dizziness.
Neshkes et al. also compared doxepin and imipramine in a parallel design study (Neshkes 1985). Thirty-six patients with ages ranging from 55 to 8l years received mean daily doses of imipramine of 83 mg and of doxepin 76 mg. The mean decrease in systolic blood pressure for imipramine and doxepin were 25 and 10 mm Hg, respectively. The decrease with doxepin was no significantly different from the placebo group.
MYOCARDIUM
Heart Rate
TCAs are usually associated with significant increases in heart rate. These effects are believed to be due to the anticholinergic action of these drugs and probably, in part, to the relative affinity of these drugs for muscarinic receptors. Ziegler et al. studied 15 patients treated with amitriptyline 75-200 mg/d for minimum of 3 weeks and noted a mean increase of 16 beats/minute (Zeigler et al 1977). The same group noted a comparable increase in heart rate (16 beats/minute) in a group of 17 patients treated with nortriptyline 50-150 mg/d for a minimum of 3 weeks (Ziegler et al 1977). Giardina et al. treated 44 patients with imipramine 3.5 mg/kg/d for 4 weeks (Giardina et al 1979). Using 24-hour monitoring, they observed an average increase of 7 beats/minute in the first week that declined to 3 beats/minute in the fourth week, suggesting tolerance develops to this effect.
Rudorfer and Young reported a statistically significant increase in mean heart rate of 15 beats/minute with desipramine (Rudorfer et al 1980). Some patient's heart rate increased to 115 beats/minute. Linnoila reported a mean increase of 8 beats/minute with doxepin (Linnoila 1982).
Conduction Effects
TCAs have similar effects on the ECG, which is attributed to their having a quinidine-like (type 1 antiarrhythmic) action. This effect is to prolong the His-Ventricular conduction but not the Atrial-His component of the PR interval. Other type 1 anti-arrhythmic drugs in this class include procainamide and disopyramide.
Amitriptyline
White et al. reported 12 patients treated with amitriptyline at a mean maximum dose of 250 mg/d had significantly prolonged PR (12.5 msec) and QTc (13.2 msec) intervals (White et al 1982).
However, Veith et al. reported that amitriptyline up to a maximum of 200 mg/d which produced mean plasma concentrations of AMI and NT of 230 ng/ml had no significant effects on the ECG (Veith et al 1982).
Imipramine
Giardina et al. studying the ECG of patients treated with imipramine 3.5 mg/kg/d for 4 weeks, observed significant prolongations of the PR interval (13.5 msec), the QRS (9.7 msec), and the QTc (16.9 msec) (Giardina et al 1979). These changes tended to increase during the study and correlated with plasma drug concentration.
The same group also reported one (0.7%) of 150 imipramine or nortriptyline completers developed 2:1 AV block, which converted to normal sinus rhythm when nortriptyline was discontinued (Roose et al 1987a). In 10 patients with only first-degree block in whom a therapeutic concentration of imipramine (n=8) or nortriptyline (n=5) was reached, there were no conduction complications. However, among the 24 patients with BBB who reached a therapeutic concentration of imipramine (n=22) and/or nortriptyline (n=15), significant conduction abnormalities occurred. Two (9%) of the 22 imipramine-treated patients developed 2:1 AV block, which reverted to NSR when the drug was discontinued. In two other patients the QRS durations increased by greater than 25% (but still less than .20s). Of the 15 patients with BBB receiving nortriptyline who reached a therapeutic concentration, one suffered a cardiac arrest and required a pacemaker. One patient with a history of an MI eight years earlier experienced a second MI. Comparing the rates of 2:1 AV block in TCA treated patients with and without normal EKGs yields a significantly (p < .05) higher rate in patients with BBB.
Nortriptyline
Reed et al. reported on 12 patients with a mean age of 68 years (range 60-78 years) who received nortriptyline 50 t.i.d. (Reed et al 1980). Five patients had EKG changes consistent with PVCs, supraventricular premature contractions, right atrial hypertrophy, Wolff-Parkinson-White syndrome, and left and right bundle branch block. Eleven patients had mean steady-state nortriptyline plasma levels of 90-160 ng/ml, which is considered within the "therapeutic window". One patient had plasma levels of 187-250 ng/ml at 150-200 mg/day and developed first-degree heart block which subsided when the plasma level was reduced to 140-180 ng/ml. The other eleven patients had no clinically significant changes in the EKG after nortriptyline was initiated. Similar findings were reported by Zeigler et al.
Vohra et al. studied 12 patients treated with nortriptyline with plasma levels in the range of 75-470 ng/ml (mean = 209) (Vohra et al 1975a). They examined the His Bundle Electrogram (HBE) to determine the site for PR prolongation. All four patients with plasma levels above 200 ng/ml developed H-V prolongation while only one out of eight, with levels below 200 ng/ml, did so (p < 0.05).
Young et al. studied 18 elderly patients, 10 of whom had ASCVD (Dietch and Fine 1990). After baseline measurements they were treated with and average nortriptyline dose of 75 mg/d. In addition to measuring plasma nortriptyline concentrations, the 10-hydroxy metabolite concentration was recorded. Prolongation of AV conduction correlated with the 10-OH metabolite alone and when combined with the plasma nortriptyline concentration. This study suggested that the 10-OH metabolite is pharmacologically active and may play a role in adverse conduction effects associated with nortriptyline.
Dietch et al studied 10 elderly depressed patients with preexisting conduction abnormalities (Dietch and Fine 1990). The patients ranged in age from 76 to 95 years and had ECG abnormalities of first degree A-V block, left and right bundle branch block, left anterior hemiblock, and/or sinus bradycardia. All patients received nortriptyline up to 75 mg/d which resulted in 9/10 patients with a steady-state serum level within the therapeutic range except one patient with a level above 160 ng/ml. Six of the 10 patient's depression responded. Except for two patients with a slight increase in the severity of first degree block, there were not significant ECG changes. The authors concluded elderly patients with the noted conduction abnormalities may receive nortriptyline safely with appropriate serum level and cardiac monitoring.
Desipramine
In the Rudorfer and Young study described earlier, statistically significant increases (p < 0.05) in PR and QRS intervals were noted in patients with "therapeutic" levels of desipramine (Rudorfer et al 1980). The ECG interval durations generally remained within normal limits, however. One PR interval was 200 milliseconds and one QRS interval was 113 milliseconds. Changes in the PR interval were significantly correlated with plasma desipramine levels (r = 0.53, p < 0.05).
However, Veith et al. reported that desipramine up to a maximum of 200 mg/d (mean plasma concentrations of 173 ng/ml) for 3 weeks in 46 patients produced a significant increase in the QRS (9 msec) and QTc (24 msec) intervals (Veith et al 1982). Changes in ECG measures did not correlate with plasma concentration of the drug.
Doxepin
Vohra et al. studied the ECG of 32 psychiatric patients on TCAs (Vohra et al 1975b). Twenty (63%) were receiving nortriptyline, 8 (25%) were on doxepin, and the other 4 received imipramine or amitriptyline. In nortriptyline-treated patients, PR interval increased in 14/20 (70%), decreased in 3/20 (15%), and remained unchanged in 3/20 (15%). However, changes in PR interval was less marked in the doxepin treated patients. The PR interval increased in 4/8 (50%), decreased in 2/8 (25%), and remained unchanged in 2/8 (25%). In this study the plasma levels of nortriptyline ranged from 60-392 ng/ml (mean = 182) i.e., most patients had a level above the "therapeutic window" of nortriptyline. The levels of doxepin were not measured, however.
The same group of authors performed a second study (Vohra et al 1975a). This was a cross-over design with 17 patients given fixed doses of doxepin or nortriptyline 150 mg/d. Again, they found a significant increase in QRS duration in the nortriptyline treatment period but not in the doxepin treatment period. However, plasma levels were 31-416 ng/ml (mean = 196) for nortriptyline i.e., supratherapeutic and < 30-118 ng/ml (mean = 52) for doxepin i.e., subtherapeutic. Therefore, with such a wide difference in plasma levels of the two drugs it is difficult to conclude that doxepin is less cardiotoxic.
Rhythm Effects
The TCAs have a well-documented antiarrhythmic effect, probably related to their quinidine-like action. Bigger et al. reported improvement in 10 of 11 patients with VPCs who were treated with imipramine 3.5 mg/kg/d (Bigger et al 1977).
Giardina et al. compared the antiarrhythmic effect of imipramine and nortriptyline (Giardina et al 1981). They administered nortriptyline to six patients and imipramine to 22 patients with VPCs. Doses were begun at 1 mg/kg/d and increased by 1 mg/kg/day every other day until greater than 80% of the PVCs were suppressed or adverse effects occurred. Imipramine (194 ± 80 mg/d) reduced the VPCs by > 80% in 17 (77%) of patients while five (83%) nortriptyline (50 ± 14 mg/d) patients experienced the same effect.
Glassman and Bigger have indicated if a depressed patient is receiving one of the Type I antiarrhythmics prior to the start of TCA treatment, the antiarrhythmic should be discontinued or the dose reduced and the ECG monitored (Glassman and Bigger 1981).
Mechanical Function
Vieth et al studied 24 depressives (RDC) with chronic heart disease (Veith et al 1981). The patients were treated for four weeks in a double-blind trial with imipramine (129 ± 57 mg/d; 147 ± 137 ng/ml), doxepin (153 ± 72 mg/d) or placebo. The left ventricular ejection fraction was unchanged at rest and at exercise for all the treatment groups. Imipramine significantly decreased the number of VPCs.
Glassman et al. studied 15 depressives with congestive heart failure (Glassman et al 1983). Performance studies involving left ventricular function suggested no drug-induced changes. However, in 7 of the 15 patients the imipramine had to be discontinued because of severe orthostatic hypotension.
Roose et al. studied 21 patients who had a history of CHF and/or a large heart on chest x-ray (Roose et al 1986). After a week of baseline testing, nortriptyline was started building the dose over 5 days to 1.4 mg/kg/d po on t.i.d. schedule. After 10 days, the dose was adjusted to achieve a plasma concentration between 50 and 150 ng/ml. Like imipramine, nortriptyline did not produce any deleterious effects on left ventricular function. However, unlike imipramine, the orthostatic drop with nortriptyline was minimal. Only one of the 21 patients developed orthostatic hypotension that required drug discontinuation. Nineteen of the 21 patients had previously been treated with imipramine, and eight of them (42%) had developed orthostatic hypotension with that tricyclic.
TCAs and Sudden Death
Utilizing the Aberdeen Drug Surveillance System, Coull et al compared the incidence of sudden deaths of a group of 53 patients who had preexisting cardiac disease and were receiving amitriptyline with another group of similar patients not receiving the TCA (Coull et al 1970). The patients were matched for age, sex, duration of hospitalization, diagnosis, history of myocardial infarction, congestive heart failure, and anemia. They found six sudden deaths in the amitriptyline-treated group but none in the nontreated group. The difference between the two groups was significant (p < 0.05, Yate's correction).
The study was extended to include 119 patients (Moir et al 1971). There were 13 (11%) unexpected deaths in the amitriptyline group (10 died of either myocardial infarction, cardiac failure, cardiac arrest, or cardiac arrhythmia), and only 3 (2.5%) in the nontreated group (2 died of myocardial infarction). Again, the difference between the two groups was significant (p < 0.02, Yate's correction). These authors concluded that while amitriptyline had a cardiotoxic effect when given in therapeutic doses to patients with pre-existing heart disease, it might not be the single contributing factor to sudden deaths in these patients. However, it was recommended that tricyclics ought to be prescribed with extreme caution in patients with acute cardiac disease.
A contradicting report was presented by the Boston Collaborative Group, which found no extra risk of cardiotoxicity in patients with pre-existing cardiovascular disease who were treated with TCA (Boston 1972). In 80 patients treated with TCA, the frequency of drug-attributed arrhythmias or heart block during or after TCA treatment was 2.5% (2/80); for nonrecipients the rate was 5.8% (233/3994). The frequency of other cardiac complications such as shock, syncope, hypotension, and congestive heart failure was the same for the two groups, i.e., 3/80 (4%), and 151/3994 (3.8%). Overall fatality rates were 5.0% (4/80) and 9.4% (374/3994), respectively.
The reasons for the difference in the Boston and Aberdeen groups are unclear. It is understood that the TCA doses used in the Boston study were lower than usual: the mean daily dose for amitriptyline was 71 mg; for imipramine, 77 mg; for desipramine, 44 mg; and for nortriptyline, 50 mg. No dosage was quoted in the Aberdeen studies, making comparison with the Boston study difficult. The Boston study included patients with cardiovascular diseases, e.g., heart block, arrhythmias, congestive heart failure, shock, syncope, and hypotension, while the Aberdeen studies only included patients with cardiac disease, myocardial infarction, cardiac failure, and arrhythmias. Another methodological difference between the two studies is that the Boston group used a prospective approach while the Aberdeen study used a retrospective one.
After showing that more cardiac patients died suddenly when treated with amitriptyline, Coull et al also studied cardiac patients receiving imipramine but could find no increase in the frequency of sudden death (Coull et al 1970).
CONCLUSION
TCAs at therapeutic doses are relatively free of serious adverse effects in depressed patients without cardiovascular disease.
The most common, potentially serious vascular complication of TCAs is orthostatic hypotension (5-10% incidence); especially in patients with conduction disturbances (32%) and impaired left ventricular performance (50%) treated with imipramine. This effect appears to be less with nortriptyline. More information is needed on the relative differences of orthostatic hypotension with other available TCAs.
In patients with preexisting first-degree AV block, there is a small risk of progressive block. The literature suggest TCAs are not contraindicated in this population, but TCA concentration and ECG monitoring is required. Weekly ECG and steady-state TCA levels after dosage adjustments are recommended. This recommendation applies to all TCAs! Patients with a preexisting BBB have a 10-fold increase in risk to develop a 2:1 AV block compared to a patient with a normal ECG. Though a TCA might safely be used in this population with the careful monitoring recommended above, alternative treatments such as ECT, an MAOI, or lithium should be considered.
Therapeutic doses of TCA have little adverse effect on left ventricular performance (i.e., a negative inotropic effect), but produce a high incidence of orthostatic hypotension. As noted above, nortriptyline is less likely to decrease blood pressure in this population.
Patients with ventricular arrhythmias are likely to have their arrhythmias improve with TCA therapy. Finally, patients receiving Type 1 antiarrhythmics (i.e., procainamide, quinidine, disopyramide, encainide, flecanide, tocainide) need close ECG monitoring and may need their antiarrhythmic treatment modified, if a TCA is added.
SECOND-GENERATION ANTIDEPRESSANTS
Maprotiline (Ludiomil)
Not surprisingly the minor structural differences between maprotiline and the TCAs have not resulted in any changes in the drug's cardiovascular pharmacologic profile when compared to the TCAs. Like the TCAs, it shows conduction delays at normal therapeutic doses and, in overdose, cardiovascular deaths associated with heart block and asystole have been reported (Edwards and Goldie 1982, Ghosh 1981, Crome and Newman 1979). Maprotiline also produces orthostatic hypotension, although data on the rate of this adverse effect are not yet available (Edwards and Goldie 1982). Falls and associated fractures have been reported and there is little to suggest that the incidence of orthostatic hypotension is significantly different from older TCAs.
In studying the cardiovascular effects of tricyclic and tetracyclic antidepressants in therapeutic doses in 66 depressed patients, no differences were noted between tricyclic and tetracyclic antidepressants in the effects on parameters studied (Burckhardt et al 1978, Raeder et al 1978). Drugs studied were trimipramine, amitriptyline, imipramine, maprotiline, and mianserin. After 3 weeks of therapy all drugs were noted to increase heart rate and PR interval, but prolongation of the QRS interval or corrected QT interval was not significant. Flattening of T-waves was observed with no changes in serum potassium, but these were reversible upon discontinuation of treatment. After 13 months of therapy all ECG values returned to normal except the heart rate which continued to be increased. There was a significant prolongation of the preejection period and a slight but insignificant shortening of the left ventricular ejection time, indicating a decrease in myocardial contractility. These returned to normal after therapy was discontinued. Even with continued treatment for an additional 4 years, these same parameters returned to normal after discontinuation. No major dysrhythmias were observed.
The effect of therapeutic doses of maprotiline and imipramine on the heart was studied in 52 depressed patients (Mielke et al 1979). The drugs produced equivalent changes which were statistically significant. Both decreased standing systolic pressure, increased standing and supine pulse rates, and lengthened the corrected QT interval. There were no changes from pre- to post-treatment echocardiograms, and follow-up treadmill stress tests in 29 patients showed no arrhythmias or ischemic changes. All initial treadmill stress tests were normal. There have been no reports to date of maprotiline causing myocardial infarction. Clinically significant differences in cardiovascular effects of maprotiline and tricyclic antidepressants remain to be conclusively demonstrated.
Amoxapine (Asendin)
Whether amoxapine's pharmacologic effect of being a noradrenergic agonist and dopamine antagonist results in a cardiovascular profile that is significantly different from the TCAs is not clear. It is difficult to accurately define the cardiovascular effects of amoxapine because both the animal and human data available are so limited. Among the reported cases of serious overdose, there have been seizures and severe neurological sequelae but few serious cardiovascular complications (Bock et al 1982, Goldberg and Spector 1982, Kulig et al 1982, Ortiz and Josef 1983, Zavodnick 1981). This would suggest that this drug might have a significantly lower degree of conduction effect; however, patients at both normal therapeutic levels and in overdoses have manifested certain cardiac alterations, including bundle branch block, premature atrial contractions, and atrial flutter (Mielke et al 1979, Ortiz and Josef 1983, Zavodnick 1981). Although the literature suggests that amoxapine might have less conduction effect, the evidence is not adequate to warrant the use of amoxapine in patients with severe preexisting conduction disease. This paucity of data also makes it difficult to draw any firm conclusions about the orthostatic effects of amoxapine as compared with other TCAs. However, there are enough case reports to indicate that amoxapine can cause orthostatic hypotension.
Trazodone (Desyrel)
In clinical studies trazodone has been associated with orthostatic hypotension. Anecdotal information suggests, however, this hypotension may be different from that usually associated with TCAs. Clinicians have reported that the orthostatic effect follows shortly after the ingestion of trazodone, is more likely to occur if the medication is taken on an empty stomach, and disappears 4 to 6 hours after the drug has been taken.
No direct comparison studies of orthostatic hypotension between trazodone and TCAs have been published.
Cardiac conduction studies in trazodone overdose in dogs indicate they tolerate much higher doses of trazodone than of a standard TCA; when the dogs do die, they die from seizures not cardiac disease (Gomoll and Byrne 1981). In humans, accidental overdoses have demonstrated no evidence of cardiac abnormalities, including conduction problems (Henry and Ali 1983, Leser et al 1983, Lippmann et al 1982).
In animal studies trazodone has not been associated with heart block or rhythm disturbance other than cardiac slowing (Brogden et al 1981). Hayes et al evaluated the ECG effects in a depressed geriatric population in a drug-free state, and weekly during treatment with trazodone, placebo, or imipramine (Hayes et al 1983). Eighteen patients underwent crossover from placebo or imipramine to trazodone. Imipramine increased resting heart rate 24% and was associated with one isolated case of ECG complications i.e., atrial fibrillation with a rapid ventricular response. The authors thought trazodone would be a safer antidepressant for treating depressed geriatric patients.
This initial experience with trazodone was encouraging and suggested that this drug might be useful in patients with conduction disease for whom a TCA might be contraindicated. In the first 11 months that trazodone was on the market, the manufacturer received eight voluntary reports of ventricular ectopy in patients taking trazodone (Janowsky et al 1983). Of these eight, four described increased VPCs and four reported instances of ventricular tachycardia (two in patients with previous episodes of ventricular tachycardia). A recent report indicated trazadone produced a nonsustained ventricular tachycardia induced by exercise (Janowsky et al 1983). In an additional report, ventricular ectopic activity increased in six (10%) of 59 patients with preexisting cardiac disease treated with trazodone (Gelenberg 1983).
Certainly, patients with preexisting cardiac disease should be closely monitored while taking trazodone. As previously noted tricyclics have quinidine-like antiarrhythmic activity which decrease the frequency of PVCs and may be a better choice in patients with PVCs disturbances.
Fluoxetine (Prozac)
Fluoxetine was marketed in the U.S. in February 1988. In comparison studies in patients without cardiovascular disease, fluoxetine has been shown to produce a modest, but significant decrease in heart rate. The drug had no effect on the PR or QRS. In comparison to amitriptyline, fluoxetine produced less orthostatic hypotension (Wernicke 1985).
The drug has not been studied in patients with cardiovascular disease and caution is recommended if it is prescribed for this depressed population.
Bupropion (Wellbutrin)
There have been no bupropion-induced EKG abnormalities reported at therapeutic doses. Bupropion was tested in 12 patients who were shown to have clinically significant orthostatic hypotension when treated with TCA. After discontinuation of the TCA all patients had resolution of blood pressure changes and symptoms that remained normal on 14 days of bupropion (Zung et al 1983). A double-blind crossover study conducted in 10 depressed patients with impaired left ventricular function contrasted cardiovascular function effects of bupropion and imipramine. The results concluded that neither bupropion or imipramine resulted in a further decrease of the ejection fraction. However, 50% of the patients receiving imipramine required discontinuation secondary to orthostatic hypotension (Roose et al 1987b).
CONCLUSION
These compounds have been marketed with little, if any, experience in patients with cardiovascular disease. Comparisons between second-generation compounds have not been performed. Until further experience through research is gained, especially in patients with preexisting heart disease, these compounds should not be viewed as a safer alternative to the TCAs in the depressed population with cardiovascular disease, especially those with conduction disturbances. Appropriate blood pressure and ECG monitoring as indicated above for the TCAs should be followed for the second-generation antidepressants.
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