Barry D. Jones on sudden death in a 27-year-old schizophrenic woman. (Can Med .... Allan Memorial Institute. McGill University and the research department.
Death attributed to ventricular arrhythmia To the editor: The following remarks pertain to the report by Drs. Guy Chouinard, A.M. Ghadirian and Barry D. Jones on sudden death in a 27-year-old schizophrenic woman (Can Med Assoc 1 119: 729, 1978). Death was attributed to ventricular fibrillation resulting from the combined ingestion of one small dose of thioridazine (100 mg), one small dose of procyclidine (2.5 mg) and one Contac eC® capsule (chlorpheniramine maleate and phenylpropanolamine hydrochloride). Also, so far as can be determined, for more than 2 months prior to the time of death the patient had consumed between 100 and 200 mg/d of thioridazine without untoward effects. While the patient was receiving the small doses of thioridazine no electrocardiographic studies were done. However, about 7 months prior to the time of death, when she was taking chlorpromazine, 900 mg/d, a routine electrocardiogram (ECG) showed flattening of the T-waves and moderate sinus tachycardia. Evidently the T-wave changes were induced by chlorpromazine and were characteristic of the type of benign malformations I have described in considerable detail elsewhere.1 Implicit in some of the statements by Chouinard and colleagues was the belief that comparable T-wave changes would have been found if an ECG had been obtained when the patient was receiving thioridazine. Because, in their view, such T-wave changes were alarming, they attempted to link the presence of this sign of anomalous ventricular repolarization with the onset of cardioplegic ventricular arrhythmia. Moreover, to establish such a relation, they perceived that the T-wave changes produced by customary doses of chlorpromazine or thioridazine were "the result of either a local anesthetic effect or a quinidine-like effect" and could be "considered an early sign of quinidine-like toxicity". On this basis they asserted also that "drugs that are considered to have a greater tendency to induce [T-wave abnormalities]
could be avoided" and that "since thioridazine and mesoridazine appear to induce electrocardiographic changes more frequently than other neuroleptics . . routine electrocardiography before and after treatment with thioridazine or mesoridazine may provide a means of screening out patients with a high risk of cardiac toxic reactions." However, their perceptions regarding the alarming nature of phenothiazine-induced T-wave changes derive from certain tenuous assumptions concerning the pathogenesis of the electrophysiologic counterpart of the T-wave abnormality. Correspondingly, these assumptions are responsible for the terminology they have used to describe the ECG abnormalities. The meaning of a term such as local anesthetic effect is important. Instead of referring to a property akin to that possessed by a volatile general anesthetic, such a term refers to an in vitro electrophysiologic effect produced by a selective group of antiarrhythmic compounds. These compounds share, aside from an analogous action on isolated cardiac muscle fibres, an anesthetic effect on isolated nerve fibres. Accordingly, on the basis of the in vitro findings in studies with dogs reported by Arita and Surawicz,2 it can be said that phenothiazines produce a local anesthetic effect akin to that produced by quinidine, procainamide and lidocaine. However, although general anesthetics, especially when used in conjunction with a potent sympathomimetic agent, can be responsible for the production of a life-threatening ventricular arrhythmia in dogs with intact hearts, it does not follow that phenothiazines that produce a local anesthetic effect in an extracorporeal setting will also favour the occurrence of a similar arrhythmia in vivo. In fact, Samet and Surawicz3 have shown that in humans there are substantial disparities between the actions of customary doses of quinidine and thioridazine in terms of either their electrocardiographic effects or their effects on cardiac function. Moreover, they showed that in humans treated with phenothiazines who did not demonstrate organic
1058 CMA JOURNAL/MAY 5, 1979/VOL. 120
heart disease, a potent sympathomimetic drug was less potent as an arrhythmogenic agent. The results of my preliminary unreported studies show that even in patients known to have coronary artery disease who have been receiving relatively small doses of thioridazine, strenuous physical exercise, which augments adrenergic activity, is not followed by any type of cardiac arrhythmia. I also found that the Twave configuration was transformed from abnormal to normal following such exercise. This is in accord with my earlier finding that a coronary constrictor (ergotamine tartrate) will abolish a thioridazine-induced T-wave abnormality in the ECG of persons in whom there is no evidence of a structural cardiac lesion.1 Finally, inasmuch as Chouinard and colleagues sought to blame the sudden death on the occurrence of ventricular fibrillation due to the combined effects of an ephedrine-like compound in the Contac .C. capsule and 100 mg of thioridazine, in my experience even the administration of repeated doses of Ornade., a preparation containing the same ingredients as are found in Contac eC®, to psychiatric patients already receiving 600 to 800 mg/d of thioridazine did not result in untoward effects. Moreover, the ECGs of these patients already contained T-wave abnormalities ordinarily identified with phenothiazine administration. MARTIN H. WENDKOS, MD Department of psychiatry and human behaviour Jefferson Medical College Thomas Jefferson University Philadelphia, Pennsylvania
References 1. WENDKOS MH: Sudden Death and Psychiatric Illness, Spectrum Pub, New York, 1978 2. ARITA M, STJRAWICZ B: Electrophysiologic effects of phenothiazines on canine cardiac fibers. J Pharmacol Exp Ther 184: 619, 1973 3. SAMET JM, SuRAwIcz B: Cardiac function in patients treated with phenothiazines. Comparison with quinidine. J Clin Pharmacol 14: 588, 1974
To the editor: Dr. Wendkos has raised a number of questions concerning the mechanism by which thioridazine, in combination with a
Contac .C. capsule, induced sudden death in a healthy young woman. He suggests that our explanation for the death is based on weak evidence and not substantiated by his findings. However, the main point of our paper was to report the relation of this woman's death to the intake of thioridazine and one Contact eC® capsule and to propose some conclusions as regards the mechanism by which these drugs might induce sudden death, in the context of evidence that thioridazine and its metabolite, mesoridazine, induce more electrocardiographic changes than other phenothiazines and are responsible for cases of fatal ventricular arrhythmias. We are aware that our hypothesis is open to criticism. However, we think that patients treated with thioridazine are at higher risk for the development of cardiotoxic reactions, some of which may be fatal. During the last 5 years one of us (G.C.) has been responsible for the long-term follow-up of 300 schizophrenic patients. In. the first 2 years, during which 20% of the patients were receiving thioridazine, two sudden deaths occurred in association with the administration of this agent, one of which was reported in our article. In contrast, during the same period no deaths were caused by the ingestion of various other phenothiazines. Furthermore, during the last 3 years, after we decided to discontinue thioridazine use, no sudden deaths have occurred. Although Dr. Wendkos reports negative findings with respect to patients receiving thioridazine alone and in combination with drugs having the same constituents as Contac eC®, he must be aware that negative findings mean little when the undesirable side effects of drugs, especially death, are considered. In addition, there were two factors that increased the risk of untoward effects in our patient, factors that Dr. Wendkos makes no reference to and seems not to have been able to detect in his "preliminary unreported studies" (possibly owing to the use of small samples). First, we showed, in a double-blind study with placebo, that women are more susceptible to T-wave changes
induced by phenothiazines after a of repolarization abnormalities promeal (a glucose load),1 as did Huston duced by phenothiazines following a and Bell,2 who found a higher fre- glucose load as compared with fastquency of T-wave abnormalities in ing.1 women than in men in a sample of We believe that these two factors, 106 patients treated with thioridazine. her sex and the glucose load, in comSecond, Alvarez-Mena and Frank3 bination with the ingestion of thiorifound that T-wave changes induced dazine and Contac .C®, led to the by phenothiazines disappeared with death of our patient. The lack of unfasting in 57 of 100 patients. This toward side effects while she was was further documented in a placebo- receiving thioridazine alone excludes controlled study in which we found a thioridazine from being the only causubstantial increase in the frequency sative factor, and we therefore con-
CMA JOURNAL/MAY 5, 1979/VOL. 120 1059
cluded that the addition of Contac eC® had caused death. Similarly, others have shown that thioridazine ingestion combined with the ingestion of tricyclic antidepressants,4 alcohol intake5 or alcohol withdrawal associated with hypokalemia6 can result in serious ventricular arrhythmias. Furthermore, although phenothiazines are generally harmless when taken in excess, thioridazine and mesoridazine are not.7 More recently Donlon and Tupin5 reported five instances of death and one of reversible total heart block resulting from an overdose of thioridazine and mesondazine. However, thioridazine is probably harmless when taken in small doses by patients at low risk those for whom a postprandial ECG shows no T-wave changes while they are receiving thioridazine. All phenothiazines are equally effective in treating schizophrenia and related psychotic conditions, but the use of thioridazine or mesoridazine requires caution since it could lead to a fatal ventricular arrhythmia in the event of an overdose (which is frequent in psychiatric patients), in combination with the use of readily available nonprescription drugs such as Contac eC® or with alcohol intake, or in a patient undergoing alcohol withdrawal who has associated hypokalemia.
6. SYDNEY MA: Ventricular arrhythmias associated with use of thioridazine hydrochloride in alcohol withdrawal. Br Med J 4: 467, 1973 7. Dwss JM, BARTLETr E, TERMINI BA:
Overdosage of psychotropic drugs: a review. Part I: major and minor tranquilizers. Dis Nerv Syst 29: 157, 1968
Henrietta Banting Memorial Fund To the editor: The Federation of Medical Women of Canada has set up a memorial fund in memory of Dr. Henrietta Banting in the hope of raising money for the Medical Women's International Scholarship Fund to help medical students of Third-World countries. Dr. Banting was a well known Canadian doctor who was active in the Medical Women's International Association and the Federation of Medical Women of Canada. She was vice-president for Canada of the former from 1962 to 1968. Interested persons can send their donations to: Henrietta Banting Memorial Fund, c/o Secretariat, Federation of Medical Women of Canada, P0 Box 9502, Ottawa, Ont. KiG 3U2. E.N. CAMBON, MD
International corresponding secretary Federation of Medical Women of Canada Ottawa, Ont.
Dr. Christiaan Barnard To the editor: It is difficult to see Pharmacology research unit how the article on Dr. Christiaan Allan Memorial Institute Barnard by D.J.R. Rowe fulfills the McGill University and the research department criteria for inclusion under the headInstitut national de in ing "Science and Art" (Can Med Asrecherche scientifique H6pital Louis-H. Lafontaine Soc J 120: 98, 1979). In the article Montreal, PQ Dr. Barnard discusses his considerable failings. Why should the Journal References add to his problems by publishing 1. CHOINARD G, ANNABLE L: Phenohis philosophy of life? abnormalities. Guy CHOUINARD, MD BARRY D. JONES, MD
thiazine-induced EGG Effect of a glucose load. Arch Gen Psychiatry 34: 951, 1977 2. HUSTON JR, BELL GE: The effect of thioridazine hydrochloride and chiorpromazine on the electrocardiogram. JAMA 198: 134, 1966 3. ALVAREZ-MENA SC, FRANK MJ: Phe-
nothiazine-induced T-wave abnormalities. JAMA 224: 1730, 1973 4. HEIMAN EM: Cardiac toxicity with antidepressant thioridazine-tricyclic combination. J Nerv Ment Dis 165: 139, 1977 S. DONLON PT, TUPIN JP: Successful suicides with thioridazine and mesoridazine. Arch Gen Psychiatry 34: 955, 1977
H. JACOBS, MB, FRcP[c]
Clinical professor in medicine Neurology unit University of Alberta
Edmonton, Alta.
"Principles of Cardiac Arrhythmias" [correction] In the review of the above-named book, the affiliation for the reviewer, Dr. D. George Wyse, was incorrect (Can Med Assoc 1 120: 419, 1979). Dr. Wyse is from the University of Calgary. - Ed.
1060 CMA JOURNAL/MAY 5, 1979/VOL. 120
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