 |
 |
|
|
|
Overall mortality in psychiatric patients is two- to five fold higher than in the general population (1,2), and life expectancy is 20% shorter in patients with schizophrenia. Among the possible causes, suicide, accident, and drug abuse have received much attention. Drug abuse may double the risk of sudden death in patients with schizophrenia (3). Although increased mortality affects both sexes, it is higher in men than in women but increases with age in both sexes. The rate of mortality is highest during the first year of hospitalization and higher than in the general population. Cardiovascular lesions play a critical role among causes of death. For example, 301 of 3623 patients with schizophrenia died within the first 10 years following diagnosis and treatment of the disease, and death had a cardiovascular cause in 61 patients (20%), 15 of whom died suddenly (1). Cardiac lesions are one of the most likely causes of sudden death in psychiatric patients because of electric membrane alterations induced by psychotropic drugs (4). The alterations produced by most, if not all, psychotropic drugs mimic those seen with antiarrhythmics. Other psychotropic drugs, such as thioridazine and droperidol, induce marked prolongation of the QTc interval (5). The UK Committee on the Safety of Medicines drew attention to the risk of myocarditis resulting from clozapine, as early as 1993 (6). La Grenade and colleagues analyzed 28 instances of myo- carditis, including 18 deaths, and 48 instances of cardiomyopathy, including 10 deaths reported to the US Food and Drug Administration (FDA) between September 1989 and December 1999 (7). Antidepressants have also been shown to cause widening of QRS complexes and prolongation of QT intervals similar to those seen with quinidine-like anti- arrhythmics (8). Serotonin uptake inhibitors are not an exception in this regard, and sudden death has been reported (9). Lithium salts can also induce severe cardiac adverse effects, including bradycardia caused by sinus dysfunction, pre- mature ventricular beats, atrioventricular blocks, and depression of T waves (10–13). In this study, we report 14 cases of unexpected sudden death in psychiatric patients treated with psychotropic drugs. PatientsFourteen instances of unexpected sudden death, as defined by the World Health Organization, were recorded in psychiatric ward patients between 1980 and 1999. These 14 instances represent all the unexpected sudden deaths that occurred in Le Vinatier and Saint Jean de Dieu hospitals during this time period. Relatives of a few additional patients who suddenly died refused autopsy on religious grounds. The characteristics of each patient are summarized in Table 1. The autopsies were carried out on 10 men (mean age 41 years, SD 11 years) and 4 women (mean age 43 years, SD 12 years). None of these patients had a history or clinical symptoms of cardiac disease, but none underwent ECG or cardiac echography prior to starting treatment with psychotropic drugs. Neuroleptics were involved in 13 instances, antidepressants in 9, and anxiolytics in 5. All patients received a combination of psychotropic drugs;1 patient was also treated with furosemide and amiodarone. In all 14 patients, toxicological analyses discarded drug overdose as cause of death. At postmortem examination, the brain and abdominal organs were normal. However, in 13 patients we found the following lesions in the heart and lungs, possibly explaining sudden death: dilated cardiomyopathy (6 patients), left ventricular hypertrophy (2 patients, 1 of which was associated with mitral prolapse and anomalies of His bundle), arrhythmogenic cardiopathy of the right ventricle (1 patient), pericarditis (1 patient), mitral prolapse (1 patient), muscular bridge on the anterior inter- ventricular artery (1 patient), and Mendelsons syndrome (1 patient). In 1 patient, no changes were seen. DiscussionThe overall mortality in psychiatric patients is two- to five fold higher than in the general population (1,2), and life expectancy is 20% shorter in patients with schizophrenia. The 14 sudden deaths of this study represent only a small percentage of patients hospitalized and treated during this time period. Over 1000 patients are treated with neuroleptics each year in these 2 hospitals. However, this percentage is likely to underestimate the actual rate of sudden deaths in patients treated with neuroleptics because 1) sudden deaths occurring at home were not recorded, and 2) when autopsy revealed another possible cause of death (for example, trauma), the heart and lungs were not examined. Nevertheless, cardiovascular lesions play a critical role in the causes of death in patients with schizophrenia. Newman and colleagues reported 301 deaths among 3623 patients with schizophrenia within the first 10 years following diagnosis and treatment of the disease. Death had a cardiovascular cause in 61 patients (20%), of whom 15 died suddenly (1). Cardiac lesions are one of the most likely causes of sudden death in psychiatric patients because of electric membrane alterations induced by psychotropic drugs (4). Unexpected sudden death in our 14 patients was presumably a result of arrhythmia, and a causal relation with drug treatment can be suspected. A single patient was not on neuroleptic treatment but was treated with furo- semide and amiodarone. The 13 remaining patients received a single or several neuroleptics. The causative role of psychotropic drugs in the development of sometimes severe and even life-threatening arrhythmias has been repeatedly suspected (14). Arrhythmias are primarily a result of alterations in cardiocyte membrane ion transfers, which produce ECG changes; alterations include widening of QRS complexes, which can result in slowed intraventricular conduction, favouring the onset of reentry arrhythmias, ventricular tachycardia or fibrillation, changes in T waves, prolongation of the QT interval, and torsades de pointes (4,15,16). In our study, as in most published studies, typical neuroleptics as well as antidepressants were suspected as a cause of death. A Finnish study described 49 instances of sudden death associated with phenothiazines (17). Prolongation of the QT interval has been reported with chlorpromazine, haloperidol, and thioridazine (18). Antidepressants prolong the QT interval and widen QRS complexes (8). As these changes are similar to those seen with antiarrhythmics, a similar impact on membrane ionic transfers can be suspected. However, sudden deaths have also been reported with atypical neuroleptics such as clozapine and olanzapine. Killian and colleagues followed 8000 patients treated with clozapine between 1993 and 1998 (19). They reported 18 examples of myocarditis, with 5 deaths, including 3 sudden deaths. Five other patients developed cardiomyopathy, and a single patient died (19). The mechanism of clozapine-induced cardiomyopathy is considered to be immune-mediated in most cases. In contrast, olanzapine can prolong the QT interval, especially in patients with underlying cardiac disease and in the elderly (20) or when enzyme-inhibiting drugs, such as fluoxetine and other serotonin reuptake inhibitors (SRIs), are present. Since olanzapine is metabolized by CYP 1A2 and to some extent by CYP 2D6, which are both inhibited by SRIs, its Cmax is increased by 74% when combined with fluvoxamine and by 32% when combined with paroxetine, fluoxetine, or sertaline (21). Thus, combining neuroleptics with enzyme-inhibiting drugs results in increased plasma and tissue neuroleptic concentrations, which can produce toxic effects. The dosage of neuroleptics in such situations must be reduced (22). In addition, olanzapine at daily dosages of 20 mg or over can prolong the PR interval, resulting in arrhythmia (23), since bradycardia and the slowing of atrioventricular conduction are risk factors for torsades de pointes. Whatever the psychotropic drug used, several factors can predispose patients to severe cardiac adverse event. The main risk factors are patient age (24); myocardic ischemia (25); nonischemic cardiac diseases, such as bradycardia, atrioventricular block, or inadequate pacemaker functioning (26); combination with hepatic drug enzyme inhibitors, potentially resulting in markedly increased plasma levels of psychotropic drugs (27); ionic disturbances, such as hypokalemia and hypomagnesemia (28); and dosage (29). The predisposing role of myocardial ischemia is well recognized. Huikuri and colleagues reported that sudden death is rare in the general population (1%) but more frequent in patients with high coronary risk (2.5%); with a history of coronary ischemic disease (6%); with congestive heart failure associated with ejection fraction under 35% (17%); with a history of cardiac arrest outside a hospital (25%); and with myocardial infarct, low ejection fraction, or ventricular tachy- cardia (> 30%) (30). Thioridazine at 30 mg/kg, but not 10 mg/kg, was reported to increase the risk of ventricular fibrillation in animals with myocardial ischemia but not in healthy animals (31). These findings can be explained by slowed ventricular conduction owing to myocardial ischemia. Premature ectopic beats, anomalies of infrahisian and intraventricular conduction, and reentry arrhythmias leading to ventricular fibrillation (caused by inhibition of Na+ entry) have been described in patients treated with a combination of perphenazine and protriptyline (32). Slow conduction, evidenced by ECG, can also lead to sudden death following administration of tricyclic antidepressants or phenothiazine derivatives (33). Disertori and colleagues confirmed the adverse role of myocardial ischemia by showing that the risk of sudden death in patients is increased when cardiac failure is caused by myocardial ischemia (34). Sudden death in patients with nonischemic cardiopathies is possible but less frequent (35). Cardiac failure associated with intraventricular conduction disorders and with dilated cardiomyopathy increases the risk (36). When no structural cardiac disease is present, the increased likelihood of lethal arrhythmia probably depends on the type of tachyarrhythmia. The risk of sudden death is not increased with monomorphic tachyarrhythmia but markedly increased with polymorphic tachyarrhythmia. When tachyarrhythmia results in hemodynamic instability, the risk of sudden death in patients is increased (37). The preexistence of right ventricular dysplasia, hypertrophic cardiomyopathy, and Brugada syndrome (right branch block associated with ST accentuation) (38) is associated with a high risk of cardiac arrhythmia. High-resolution ECG is useful to identify at-risk patients, in particular those with depolarization anomalies (for example, widening of QRS complexes), by detecting small potentials at the terminal end of QRS complexes, which indicates conduction anomalies and an increased risk of ventricular tachyarrhythmia following administration of psychotropic drugs (39). In our series of 14 subjects, 2 major features can be emphasized: first, the confirmed role of risk factors, since 13 subjects had hidden cardiac lesions identified at postmortem examination; and second, the role of neuroleptics, since 2 patients were treated with haloperidol, 5 patients were treated with levomepromazine, and 3 patients received both medications. The originality of our results lies in the postmortem identification of hidden preexisting cardiac lesions. Similar findings are described in 8 patients who died suddenly and unexpectedly approximately 1 year after starting high-dosage treatment with phenothiazine derivatives and in whom ultrastructural cardiac lesions were found (40). Recently, anomalies in genes coding for sodium channels, such as the SCN5A gene, have been shown to contribute to ventricular fibrillation (41). Some of our subjects had dilated cardiomyopathy. The question arises whether neuroleptics induced cardiomyopathy. Several neuroleptics, such as thioridazine and to a lesser extent haloperidol, are potent inhibitors of calmodulin, an intracellular calcium-binding protein (42), which could result in lesions leading to toxic cardiomyopathy. However, this hypothesis needs to be confirmed. Disorders of cardiac repolarization, including anomalies of U wave, large U wave, and prolongation of the QT interval, are commonly associated with sudden death and are caused by psychotropic drugs (4). Many psychotropic drugs, including neuroleptics (43,44) and tricyclic (45) and tetracyclic (46) antidepressants, have been shown to cause torsades de pointes. The delay in ventricular repolarization caused by psychotropic drugs is evidenced as prolongation of the QT interval. This prolongation is considered the major risk marker of torsades de pointes. The delay in K+ ions outflow is the cause of prolonged duration in the action potential and in repolarization disorders resulting in torsades de pointes. Drugs that interfere with the potassium channel, especially the IKr component, can cause early depolarizing postpotentials leading to torsades de pointes (47). Drug-induced torsades de pointes develops preferentially when risk factors are present; these include hypokalemia, which alters the membrane potential and induces a shift closer to the depolarization threshold (48), sinus bradycardia, and atrioventricular blocks (26). This review highlights the role of psychotropic drugs in sudden death, especially when preexisting risk factors are present. Unexpected sudden death in our 14 patients was likely caused by ventricular fibrillation resulting from reentry arrhythmia or torsades de pointes. At autopsy, 13 of these 14 patients had hidden cardiac lesions. Importantly, death in these patients probably resulted not only from prolongation of the QT interval caused by inhibition of potassium outflow but also from reentry arrhythmia caused by inhibition of the sodium channel. The likelihood of a severe cardiac accident developing is greatest when one or more risk factors are present. One limitation of our study is that none of the patients were evaluated by ECG or hemodynamics. Ionic plasma concentrations were measured only rarely and never prior to the start of neuroleptic treatment. No preexisting anomaly could therefore be identified. However, autopsy evidenced arrhyth- mogenic lesions that can be considered as the likely cause of sudden death in these patients. Since no hemodynamic evaluation (for example, cardiac echography) occurred, it is not possible to know whether neuroleptics progressively induced dilated cardiomyopathy via their suggested effect on calmodulin, an intracellular calcium-binding protein (42), and led to toxic cardiomyopathy. Further studies are warranted to confirm this hypothesis. Sudden death in patients treated by neuroleptics is caused by ventricular fibrillation, which is the final consequence of 1) anomalies of depolarization, which requires analysis of QRS complexes and measurement of natremia, since hyponatremia enhances the risk of reentry arrhythmia; or 2) anomalies of repolarization, which requires measurement of the QT interval and of kalemia, since hypokalemia enhances the risk of torsades de pointes. Thus, we recommend ECG and measurement of serum ion levels prior to starting any psychotropic treatment. AcknowledgementThe authors thank Brigitte Tourlière for her helpful assistance in the literature search. References1. Newman SC, Bland RC. Mortality in a cohort of patients with schizophrenia: a record linkage study. Can J Psychiatry 1991;36:239–45. 2. Ruschena D, Mullen PE, Burgess P, Cordner SM, Barry-Walsh J, Drummer OH, and others. Sudden death in psychiatric patients. Br J Psychiatry 1998;172:331–6. 3. Hansen V, Arnessen E, Jacobsen BK. Total mortality in people admitted to a psychiatric hospital. Br J Psychiatry 1997;170:186–90. 4. Di-Giacomo J. Cardiovascular effects of psychotropic drugs. Cardiovasc Rev Rep 1989;10:31–47. . Reilly JG, Ayis SA, Jones SJ, Thomas SHL. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000;355:1048–52. 6. Committee of Medicines/Medicines Control Agency. Drug induced neutropenia and agranulocytosis. Current problems 1993; 19: 10–11 7. La Grenade L, Graham D, Trontell A. Myocarditis and cardiomyopathy associated with clozapine use in the United States. N Engl J Med 2001;345:224. 8. Blackwell B. Antidepressant drugs. In: Dukes MNG, editor. Side-effects of drugs annual 10. Amsterdam: Elsevier; 1986. p 15–26 9. Spier SA, Frontera MA. Unexpected death in depressed medical inpatients treated with fluoxetine. J Clin Psychiatry 1991;52:377–82. 10. Montalescot G, Levy H, Hatt PY. Serious sinus node dysfunction caused by therapeutic doses of lithium. Int J Cardiol 1984;5:94–6. 11. Palileo EV, Coelho A, Westveer D, Dhingra R, Rosen KM. Persistent sinus node dysfunction secondary to lithium therapy. Am Heart J 1983;106:1443–4. 12. Martin CA, Pisascik MT. First A-V block in patients on lithium carbonate. Can J Psychiatry 1985;30:114–6. 13. Demers RG, Heninger GR. Electrographic T-wave changes during lithium carbonate treatment. JAMA 1971;218:381–6 14. Snaith RP. Antipsychotic polypharmacy and early death. Br J Psychiatry 1999;174:368–9. 15. Warner JP, Barnes TR, Henry JA. Electrocardiographic changes in patients receiving neuroleptic medication. Acta Psychiatr Scand 1996;93:311–3. 16. Drici MD, Wang WX, Liu XK, Woosley RL, Flockhart DA. Prolongation of QT interval in isolated feline hearts by antipsychotic drug. J Clin Psychopharmacol 1998;18:477–81 17. Mehtonen OP, Aranko J, Malkonen L, Vapaatalo H. A survey of sudden death associated with the use of antipsychotic or antidepressant drug: 49 cases in Finland. Acta Psychiatr Scand 1991;84:58–64 18. Timell AM. Thioridazine: re-evaluating the risk/benefit equation. Ann Clin Psychiatry 2000;12:147–51. 19. Killian JG, Kerr K, Lawrence C, Celermajer DS. Myocarditis and cardio- myopathy associated with clozapine. Lancet 1999;354:1841–5. 20. Gupta N, Malhotra P. Olanzapine: a proarrhythmic drug? Can J Psychiatry 2002;47:683–4. 21. Gex-Fabry M, Balant-Gorgia AE, Balant RP. Therapeutic drug monitoring of olanzapine: the combined effect of age, gender, smoking, and comedication. Ther Drug Monit 2003;25:46–53. 22. Ketai R. Interaction between fluoxetine and neuroleptics. Am J Psychiatry 1993;150:836–7. 23. Kosky N. A possible association between normal and high dose olanzapine and prolongation of the PR interval. J Psychopharmacol 2002;2:181–2. 24. Harris MG, Benfield P. Fluoxetine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in older patients with depressive illness. Drugs Aging 1995;64–84. 25. Roden DM. Torsades de pointes. Clin Cardiol 1993;16:683–6. 26. Kurita T, Ohe T, Marui N, Aihara N, Takaki H, Kamakura S, and others. Bradycardia-induced abnormal QT prolongation in patients with complete atrioventricular block with torsades de pointes. Am J Cardiol 1992;69:628–33. 27. Jerling M, Merle Y, Mentre F, Mallet A. Population pharmacokinetics of nortriptyline during monotherapy and concomitant treatment with drugs that inhibit CYP-2D6: an evaluation with nonparametric maximum likelihood method. Br J Clin Pharmacol 1994;38:453–62 28. Dyckner T, Wester PO. Ventricular extrasystoles and intracellular electrolytes before and after potassium and magnesium infusion in patients on diuretic treatment. Am Heart J 1979;97:12–8 29. Ray WA, Meredith S, Thapa PB, Meador KG, Hall K, Murray KT. Antipsychotics and sudden cardiac death. Arch Gen Psychiatry 2001;58:1168–71 30. Huikuri HV, Castellanos A, Myerburg JJ. Sudden death due to cardiac arrhythmias. N Engl J Med 2001;345:1473–82. 31. Davis JC, Bigger JT. The effects of thioridazine on electrical and ischemic ventricular fibrillation in the dog heart in situ. J Pharmacol Exp Ther 1981;216:39–44 32. Magorien RD, Jewell GM, Schaal SF. Electrophysiologic studies of perphenazine and protriptyline in a patient with psychotropic drug-induced ventricular fibrillation. Am J Med 1979;67:353–7. 33. Glassman AH, Bigger JT. Cardiovascular effects of therapeutic doses of tricyclic antidepressants. Arch Gen Psych 1981;38:815–20. 34. Disertori M, Dallafior D, Marini M. Arrhythmia risk stratification based on etiological and anatomo-structural factors. Ital Heart J 2001;2:1265–9. 35. Baldasseroni S, Opasich C, Gorini M, Lucci D, Marchionni N, Marini M, and others. Left bundle-branch block is associated with increased 1-year sudden and total mortality rate in 5517 outpatients with congestive heart failure: a report from the Italian network on congestive heart failure. Am Heart J 2002;143:398–405 36. Bansch D, Antz M, Boczor S, Volkmer M, Tebbenjohanns J, Seidl K, and others. Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy: the Cardiomyopathy Trial (CAT). Circulation 2002;105:1453–8. 37. Sarter BH, Finle JK, Gerszten RE, Buxton AE. What is the risk of sudden cardiac death in patients presenting with hemodynamically stable sustained ventricular tachycardia after myocardial infarction? J Am Coll Cardiol 1996;28:122–9 38. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol 1992;20:1391–6. 39. Brembilla-Perrot B, Beurrier D, Jacquemin L, Malak S, Danchin N. Quinidine and high amplification ECG. Ann Cardiol Angeiol 1997;46:15–20. 40. Yang CP, Guillan RA. Sudden death syndrome: report of 16 patients on high doses of phenothiazine. J Kans Med Soc 1979;80:547–63 41. Chen Q, Kirsch GE, Zhng D, Brugada R, Brugada J, Brugada P, and others. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998;392:293–6. 42. Hull BE, Lockwood TD. Toxic cardiomyopathy: the effect of antipsychotic antidepressant drug and calcium on myocardial protein degradation and structural integrity. Toxicol Appl Pharmacol 1986;86:308–24. 43. Hunt N, Stern TA. The association between intravenous haloperidol and torsades de pointes. Three cases and literature review. Psychosomatics 1995;36:541–9. 44. Ravin S, Levenson J. Fatal cardiac event following initiation of risperidone therapy. Ann Pharmacother 1997;31:867–70. 45. Waslick B. Cardiac effects of desipramine. J Am Acad Child Adolesc Psychiatry 1995;34:125–6. 46. Hermann HC, Kaplan LM, Bierer BE. QT prolongation and torsades de pointes produced by tetracyclic antidepressant agent maprotiline. Am J Cardiol 1983;51:904–6. 47. Cranefield PF, Aronson RS. Torsades de pointes and early after depolarizations. Cardiovasc Drugs Ther 1991;5:531–7. 48. Carmeliet EK. Channels and control of ventricular repolarization in the heart. Fundam Clin Pharmacol 1993;7:19–28. Author(s)Manuscript received August 2002, revised, and accepted June 2003. 1. Senior Psychiatric Physician, Centre Hospitalier le Vinatier, Bron, France 2. SHead of Psychiatric Department, Centre Hospitalier le Vinatier, Bron, France 3. Head of Pharmacy Department, Centre Hospitalier le Vinatier, Bron, France 4. Head of Internal Medicine Department, Centre Hospitalier le Vinatier, Bron, France 5. Senior Physician, Forensic Medicine Department, Hôpital Louis Pradel, Bron, France 6. Senior Psychiatric Physician, Centre Hospitalier Paul Guiraud, Villejuif, France 7. Senior Psychiatric Physician, Centre Hospitalier Saint Jean de Dieu, Lyon, France. 8. Senior Physician, Centre Antipoison - Centre de Pharmacovigilance, Lyon, France. 9. Head of Centre Antipoison, Centre de Pharmacovigilance, Lyon, France 10. Head of Pharmacology Department, faculté de médecien, Centre de Pharmacovigilance, Lyon, France Address for correspondence: Dr Q Timour, Centre Antipoison-Centre de Pharmacovigilance, 162 avenue Lacassagne, Lyon cedex 03, e-mail: quadiri.timour@chu-lyon.fr
1 | 2
|
||||||