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Noninvasive measurement of cardiac ejection fraction during desipramine treatment
CASE REPORT
MICHELE MURBURG, M.D. RAYMOND F. ANTON, M.D. J. CRAIG NELSON, M.D. PETER I. JATLOW, M.D.
Noninvasive measurement of cardiac ejection fraction during desipramine treatment The cardiovascular effects of the tricyclic antidepressants (TCAs) include tachycardia, hypotension, and conduction and repolarization disturbances. ' -4 Both positive and negative effects on myocardial contractility have been described. Much of our understanding of the effects ofTCAs on the cardiovascular system derives from experimental work in dogs. Increased myocardial contractility occurred at low intravenous doses of imipramine, with decreased contractility at higher doses. s Desipramine, the demethylated metabolite of imipramine, increased heart· rate and cardiac force, and potentiated chronotropic, inotropic, and pressor responses to exogenous norepinephrine. 6 Continuous infusion, however, produced myocardial depression that could be reversed by ouabain. 7 TCAs thus seem in the dog to have a biphasic effect on the heart: low doses stimulate while high doses Dr. Murburg is chief resident in psychiatry at Yale University School of Medicine. Dr. Anton is staff psychiatrist at the Veterans Administration Medical Center, Charleston, SC, and assistant professor of psychiatry at the Medical University of South Carolina. Dr. Nelson is associate professor ofpsychiatry, and Dr. latlow is professor of laboratory medicine and psychiatry, both at Yale University School of Medicine. Reprint requests to Dr. Anton, Psychiatry Service, VA Medical Center, 109 Bee St, Charleston, SC 29403.
JULY 1982· VOL 23· NO 7
to the contrary depress cardiac contractility. In humans, although the effects of TCAs on cardiac conduction are well accepted, their effect on cardiac contractility remains open to interpretation. At up to 150 mg, nortriptyline causes a negative inotropic effect, documented by increase in the pre-ejection period relative to the left ventricular ejection time. 8 The negative inotropic effect correlated positively with plasma nortriptyline concentration. Case reports suggesting that imipramine might cause congestive heart failure in patients with pre-existing cardiovascular disease support the concept that decreased cardiac contractility is caused by TCAs.9 However, since severe postural hypotension was present in patients with congestive heart failure, a direct cardiac effect is not certain. While the previous data tend to support a negative inotropic effect during administration of therapeutic doses of TCAs, data from patients after large acute doses of TCAs do not support this finding. After tricyclic antidepressant overdose. ten patients did not manifest hemodynamic evidence of myocardial failure. 1U Five patients without cardiac disease, who were hemodynamically monitored following TCA overdose, showed similar results." The effects of TCAs on the myocardium may be time- as well as dose-dependent. Their influence on cardiac illness cannot reliably be predicted, because of 759
Case report
inconsistent data in the literature. Because of concern about the possible negative inotropic effect ofTCAs, we used M-mode echocardiography to obtain serial measurements of cardiac ejection fraction during desipramine treatment of a depressed patient with aortic stenosis. Case report A 69-year-old married man referred for inpatient treatment of a depressive syndrome displayed anorexia, weight loss, middle and late insomnia, anhedonia, poor energy, psychomotor retardation, hopelessness, guilty ruminations, and preoccupation with somatic concerns. He had calcific aortic stenosis and concentric left ventricular hypertrophy documented by echocardiogram and chest x-ray. Digoxin (0.25 mg daily) and hydrochlorothiazide (50 mg daily) had been prescribed a year previously, after which signs and symptoms of congestive heart failure had subsided. The patient had no history of angina pectoris or myocardial infarction. Physical examination revealed a systolic murmur consistent with aortic stenosis. Pretreatment ECG showed left ventricular hypertrophy, but was otherwise normal. The ejection fraction and left ventricular motion were normal by echocardiogram prior to desipramine treatment. We administered desipramine in divided daily doses (tid at low dosages and qid at dosages exceeding 200 mg per day) for 75 days, with dosage increases every 14 to 21 days to a maximum daily dosage of 350 mg. Further assessments included measurement of blood pressure and pulse twice daily, and recording of echocardiograms after every dosage change. We determined steady-state desipramine concentrations after the patient had been on the same oral dosage for at least seven days. Blood samples were drawn in the morning 11 hours subsequent to the last dose. We
,.---------- ---,,
,
-------.
/
/
,fI
50
100
150
Steady-state desipramine plasma concentration (ng/ml)
FIGURE-Effect of desipramine on systolic ejection fraction in a patient with aortic stenosis. 760
determined plasma desipramine concentrations with a modification of the gas chromatographic-nitrogen detector method described by Bailey and Jatlow,12 and measured ejection fractions after the patient had been taking the same oral dose for seven to 15 days. We found no consistent changes in this man's pulse, blood pressure, or ECG, including OT interval, as plasma desipramine concentrations increased. As the Figure shows, the ejection fraction remained within normal limits (normal EF ;:::60%), as plasma desipramine levels increased. Dosages of other medications affecting cardiovascular status were held constant. The patient remained without evidence of congestive heart failure throughout the treatment period, and showed improvement in depressive symptoms at a plasma desipramine level of 150 ng/ml, which was finally achieved with a daily desipramine dosage of 350 mg in this 77-kg man.
Discussion This case tends to support the concept that desipramine can be used safely in a patient with aortic stenosis and congestive heart failure. We did not find evidence of decreased cardiac contractility at therapeutic plasma levels of desipramine. However, this man was maintained on digoxin, which may have provided some prophylactic effect similar to that exhibited by ouabain during acute infusion of desipramine in dogs.? We used a high dosage of desipramine to achieve the plasma levels necessary for therapeutic effect. Repeated assessment of ECG and echocardiographic ejection fraction, together with monitoring of pulse and blood pressure, provided evidence of stable cardiovascular status. Since concentrations of tricyclic antidepressants are higher in the myocardium than in plasma,13 it can be highly desirable to assess cardiac function as well as plasma TCA concentration in order to confirm lack of toxicity in patients with cardiac disease. Further studies may clarify the extent and nature of cardiac toxicity associated with the use of tricyclic antidepressants in patients with different types of valvular and coronary heart disease. Until those data become available, noninvasive monitoring of cardiovascular status, using ECG and echocardiography, in conjunction with assessment of tricyclic antidepressant concentrations, can assist physicians in safely and adequately treating depression in patients with heart disease. [J
REFERENCES 1. Raistield IH: Cardiovascular complications of antidepressant therapy. Am Heart J 83: 129-133. 1972.
PSYCHOSOMATICS
2. Jefferson JW: A review of the cardiovascular effects and toxicity of tricyclic antidepressants. Psychosom Med 37:t60-t79. 1975. 3. Vohra J. Burrows G. Hunt D. et al: The effect of toxic and therapeutic doses of tricyclic antidepressant drugs on intracardiac conduction. Eur J Cardio/3:2t9-227. 1975. 4. Burrows GO. Vohra J. Hunt D. et al: Cardiac effects of different tricyclic antidepressant drugs. Br J Psychiatry 129:335-341. 1976. 5. Sigg EB. Osborne M. Korol B: Cardiovascular effects of imipramine. J Pharmacol Exp Ther 141 :237-243. t963. 6. Kaumann A. Basso N. Aramendia P: The cardiovascular effects of N-(gamma-methylaminopropyl-imirlO-dibenzyl)-HCI (desmethylimipramine) and guanethidine. J Pharmacol Exp Ther 147:54-64. 1965 7. Laddu AR. Somani P: Desipramine toxicity and its treatment. Toxicol Appl Pharmaco/15:287-294.1969. 8. Taylor JE. Braithwaite RA: Cardiac effects of tricyclic antidepressant
9.
10. 11. 12.
13.
medication (A preliminary study of nortriptyline). Br Heart J 40:10051009.1978. Muller OF. Goodman N. Bellet S: The hypotensive effect of imipramine hydrochloride in patients with cardiovascular disease. Clin Pharmacol Ther 2:300-307. 1961. Thorstrand C: Cardiovascular effects of poisoning wifh tricyclic antidepressants. Acta Med Scand 195:505-514.1974. Langou RA. Van Dyke C. Tahan SR. et al: Cardiovascular manifestations of tricyclic antidepressant overdose. Am Heart J 100:458-464. 1980. Bailey ON. Jatlow PI: Gas-chromatographic analysis for therapeutic concentrations of imipramine and desipramine in plasma. with use of a • nitrogen detector. Clin Chem 22:1697-1701. 1976. Dingell JV. Sulser F. Gillette JR: Species differences in the metabolism of imipramine and desmefhylimipramine (DMI). J Pharmacol Exp Ther 143:14-22.1964.
29th Annual Meeting Academy of Psychosomatic Medicine Chicago • November 18-21, 1982 Speakers and workshops will focus on the interface between medicine and the behavioral sciences, including therapeutic strategies that utilize psychological, behavioral, or pharmacologic modalities. Therapeutic strategies in: -Type A behavior -Occupational health
-Eating behaviors -Addictive behaviors
-Sexuality -Sleep problems
Treatment of illness and prevention of morbidity in the following areas: -Cardiovascular -Endocrinologic
-Gastrointestinal -Dermatologic
-Respiratory -Neurologic
-Nephrologic -Oncologic
And featuring a special one-day symposium: Psychosomatic Geriatrics in the 1980s An overview of current diagnostic and treatment approaches with outstanding speakers from the University of Chicago, Harvard, University of Minnesota, Johns Hopkins, U.c.LA, Mayo Medical School, and the National Institute on Aging For complete program and registration materials, contact Academy of Psychosomatic Medicine 70 West Hubbard Street, Suite 202 Chicago, Il60610· Phone: 312-644·2623
JULY 1982, VOL 23· NO 7
761
MICHELE MURBURG, M.D. RAYMOND F. ANTON, M.D. J. CRAIG NELSON, M.D. PETER I. JATLOW, M.D.
Noninvasive measurement of cardiac ejection fraction during desipramine treatment The cardiovascular effects of the tricyclic antidepressants (TCAs) include tachycardia, hypotension, and conduction and repolarization disturbances. ' -4 Both positive and negative effects on myocardial contractility have been described. Much of our understanding of the effects ofTCAs on the cardiovascular system derives from experimental work in dogs. Increased myocardial contractility occurred at low intravenous doses of imipramine, with decreased contractility at higher doses. s Desipramine, the demethylated metabolite of imipramine, increased heart· rate and cardiac force, and potentiated chronotropic, inotropic, and pressor responses to exogenous norepinephrine. 6 Continuous infusion, however, produced myocardial depression that could be reversed by ouabain. 7 TCAs thus seem in the dog to have a biphasic effect on the heart: low doses stimulate while high doses Dr. Murburg is chief resident in psychiatry at Yale University School of Medicine. Dr. Anton is staff psychiatrist at the Veterans Administration Medical Center, Charleston, SC, and assistant professor of psychiatry at the Medical University of South Carolina. Dr. Nelson is associate professor ofpsychiatry, and Dr. latlow is professor of laboratory medicine and psychiatry, both at Yale University School of Medicine. Reprint requests to Dr. Anton, Psychiatry Service, VA Medical Center, 109 Bee St, Charleston, SC 29403.
JULY 1982· VOL 23· NO 7
to the contrary depress cardiac contractility. In humans, although the effects of TCAs on cardiac conduction are well accepted, their effect on cardiac contractility remains open to interpretation. At up to 150 mg, nortriptyline causes a negative inotropic effect, documented by increase in the pre-ejection period relative to the left ventricular ejection time. 8 The negative inotropic effect correlated positively with plasma nortriptyline concentration. Case reports suggesting that imipramine might cause congestive heart failure in patients with pre-existing cardiovascular disease support the concept that decreased cardiac contractility is caused by TCAs.9 However, since severe postural hypotension was present in patients with congestive heart failure, a direct cardiac effect is not certain. While the previous data tend to support a negative inotropic effect during administration of therapeutic doses of TCAs, data from patients after large acute doses of TCAs do not support this finding. After tricyclic antidepressant overdose. ten patients did not manifest hemodynamic evidence of myocardial failure. 1U Five patients without cardiac disease, who were hemodynamically monitored following TCA overdose, showed similar results." The effects of TCAs on the myocardium may be time- as well as dose-dependent. Their influence on cardiac illness cannot reliably be predicted, because of 759
Case report
inconsistent data in the literature. Because of concern about the possible negative inotropic effect ofTCAs, we used M-mode echocardiography to obtain serial measurements of cardiac ejection fraction during desipramine treatment of a depressed patient with aortic stenosis. Case report A 69-year-old married man referred for inpatient treatment of a depressive syndrome displayed anorexia, weight loss, middle and late insomnia, anhedonia, poor energy, psychomotor retardation, hopelessness, guilty ruminations, and preoccupation with somatic concerns. He had calcific aortic stenosis and concentric left ventricular hypertrophy documented by echocardiogram and chest x-ray. Digoxin (0.25 mg daily) and hydrochlorothiazide (50 mg daily) had been prescribed a year previously, after which signs and symptoms of congestive heart failure had subsided. The patient had no history of angina pectoris or myocardial infarction. Physical examination revealed a systolic murmur consistent with aortic stenosis. Pretreatment ECG showed left ventricular hypertrophy, but was otherwise normal. The ejection fraction and left ventricular motion were normal by echocardiogram prior to desipramine treatment. We administered desipramine in divided daily doses (tid at low dosages and qid at dosages exceeding 200 mg per day) for 75 days, with dosage increases every 14 to 21 days to a maximum daily dosage of 350 mg. Further assessments included measurement of blood pressure and pulse twice daily, and recording of echocardiograms after every dosage change. We determined steady-state desipramine concentrations after the patient had been on the same oral dosage for at least seven days. Blood samples were drawn in the morning 11 hours subsequent to the last dose. We
,.---------- ---,,
,
-------.
/
/
,fI
50
100
150
Steady-state desipramine plasma concentration (ng/ml)
FIGURE-Effect of desipramine on systolic ejection fraction in a patient with aortic stenosis. 760
determined plasma desipramine concentrations with a modification of the gas chromatographic-nitrogen detector method described by Bailey and Jatlow,12 and measured ejection fractions after the patient had been taking the same oral dose for seven to 15 days. We found no consistent changes in this man's pulse, blood pressure, or ECG, including OT interval, as plasma desipramine concentrations increased. As the Figure shows, the ejection fraction remained within normal limits (normal EF ;:::60%), as plasma desipramine levels increased. Dosages of other medications affecting cardiovascular status were held constant. The patient remained without evidence of congestive heart failure throughout the treatment period, and showed improvement in depressive symptoms at a plasma desipramine level of 150 ng/ml, which was finally achieved with a daily desipramine dosage of 350 mg in this 77-kg man.
Discussion This case tends to support the concept that desipramine can be used safely in a patient with aortic stenosis and congestive heart failure. We did not find evidence of decreased cardiac contractility at therapeutic plasma levels of desipramine. However, this man was maintained on digoxin, which may have provided some prophylactic effect similar to that exhibited by ouabain during acute infusion of desipramine in dogs.? We used a high dosage of desipramine to achieve the plasma levels necessary for therapeutic effect. Repeated assessment of ECG and echocardiographic ejection fraction, together with monitoring of pulse and blood pressure, provided evidence of stable cardiovascular status. Since concentrations of tricyclic antidepressants are higher in the myocardium than in plasma,13 it can be highly desirable to assess cardiac function as well as plasma TCA concentration in order to confirm lack of toxicity in patients with cardiac disease. Further studies may clarify the extent and nature of cardiac toxicity associated with the use of tricyclic antidepressants in patients with different types of valvular and coronary heart disease. Until those data become available, noninvasive monitoring of cardiovascular status, using ECG and echocardiography, in conjunction with assessment of tricyclic antidepressant concentrations, can assist physicians in safely and adequately treating depression in patients with heart disease. [J
REFERENCES 1. Raistield IH: Cardiovascular complications of antidepressant therapy. Am Heart J 83: 129-133. 1972.
PSYCHOSOMATICS
2. Jefferson JW: A review of the cardiovascular effects and toxicity of tricyclic antidepressants. Psychosom Med 37:t60-t79. 1975. 3. Vohra J. Burrows G. Hunt D. et al: The effect of toxic and therapeutic doses of tricyclic antidepressant drugs on intracardiac conduction. Eur J Cardio/3:2t9-227. 1975. 4. Burrows GO. Vohra J. Hunt D. et al: Cardiac effects of different tricyclic antidepressant drugs. Br J Psychiatry 129:335-341. 1976. 5. Sigg EB. Osborne M. Korol B: Cardiovascular effects of imipramine. J Pharmacol Exp Ther 141 :237-243. t963. 6. Kaumann A. Basso N. Aramendia P: The cardiovascular effects of N-(gamma-methylaminopropyl-imirlO-dibenzyl)-HCI (desmethylimipramine) and guanethidine. J Pharmacol Exp Ther 147:54-64. 1965 7. Laddu AR. Somani P: Desipramine toxicity and its treatment. Toxicol Appl Pharmaco/15:287-294.1969. 8. Taylor JE. Braithwaite RA: Cardiac effects of tricyclic antidepressant
9.
10. 11. 12.
13.
medication (A preliminary study of nortriptyline). Br Heart J 40:10051009.1978. Muller OF. Goodman N. Bellet S: The hypotensive effect of imipramine hydrochloride in patients with cardiovascular disease. Clin Pharmacol Ther 2:300-307. 1961. Thorstrand C: Cardiovascular effects of poisoning wifh tricyclic antidepressants. Acta Med Scand 195:505-514.1974. Langou RA. Van Dyke C. Tahan SR. et al: Cardiovascular manifestations of tricyclic antidepressant overdose. Am Heart J 100:458-464. 1980. Bailey ON. Jatlow PI: Gas-chromatographic analysis for therapeutic concentrations of imipramine and desipramine in plasma. with use of a • nitrogen detector. Clin Chem 22:1697-1701. 1976. Dingell JV. Sulser F. Gillette JR: Species differences in the metabolism of imipramine and desmefhylimipramine (DMI). J Pharmacol Exp Ther 143:14-22.1964.
29th Annual Meeting Academy of Psychosomatic Medicine Chicago • November 18-21, 1982 Speakers and workshops will focus on the interface between medicine and the behavioral sciences, including therapeutic strategies that utilize psychological, behavioral, or pharmacologic modalities. Therapeutic strategies in: -Type A behavior -Occupational health
-Eating behaviors -Addictive behaviors
-Sexuality -Sleep problems
Treatment of illness and prevention of morbidity in the following areas: -Cardiovascular -Endocrinologic
-Gastrointestinal -Dermatologic
-Respiratory -Neurologic
-Nephrologic -Oncologic
And featuring a special one-day symposium: Psychosomatic Geriatrics in the 1980s An overview of current diagnostic and treatment approaches with outstanding speakers from the University of Chicago, Harvard, University of Minnesota, Johns Hopkins, U.c.LA, Mayo Medical School, and the National Institute on Aging For complete program and registration materials, contact Academy of Psychosomatic Medicine 70 West Hubbard Street, Suite 202 Chicago, Il60610· Phone: 312-644·2623
JULY 1982, VOL 23· NO 7
761