REVIEW ARTICLES

SUDDEN DEATH IN PSYCHIATRIC DISORDERS Alina Beldie1 Abstract: Psychiatric patients are at greater risk of sudden death, with a 3–5 fold increase compared with the nonpsychiatric population. Sudden death may arise from complications of the mental illnesses or as a result of psychotropic medication. Anorexia nervosa, drug use, alcohol misuse are the mental disorders most likely associated with sudden death. A variety of psychotropic drugs, particularly antipsychotic agents and tricyclic antidepressants are associated with sudden death. Inducing cardiac arrhythmias are one of the most likely mechanisms of sudden death because of electric membrane alterations induced by psychotropic drugs, resulting in electrocardiogram changes. Psychotropic medication is not necessarily causative for excess mortality in psychiatric patients as higher doses might be linked with mortality through a contradictory factor such as worse physical condition in people with more serious mental health problems. Compared with non-suicide mortality, the number of deaths that might be attributable to medication is small, but according to most researchers, iatrogenic mortality must be taken seriously, with appropriate steps taken towards prevention. Key words: unexpected death; mental illnesses; QT interval prolongation.

Rezumat: Pacienþi psihiatrici sunt de 3-5 ori mai expusi riscului de moarte subitã, comparativ cu populaþia neafectatã de bolile psihice. Moarte subitã poate apãrea ca urmare a unor complicaþii ale bolilor mintale sau în urma administrãrii medicaþiei psihotrope. Anorexie nervoasa, uzul de droguri, uzul maladaptativ de alcool sunt tulburãri psihice, cu probabilitatea cea mai mare de asociere cu moartea subitã. O varietate de medicamente psihotrope, în special antipsihoticele ºi antidepresive triciclice sunt asociate cu moarte subitã. Inducerea aritmiilor cardiace este unul dintre mecanismele cele mai probabile de moarte subitã datoritã unor dezechilibrelor electrice ale membranei celulare provocate de medicamentele psihotrope, reflectate de modificãri ale electrocardiogramei. Medicamentele psihotrope nu sunt neaparat cauzative pentru mortalitatea crescutã la pacienþii psihiatrici deoarece decesele survenite la doze medicamentoase mari pot asocia diferite condiþii foavorizante, cum ar fi o condiþie fizicã precarã la pacienþi cu probleme grave de sãnãtate mintalã.Comparativ cu cauzele non-sinucidare de deces, numãrul de decese atribuibile administrãrii medicaþiei este mic, dar majoritatea cercetãtorilor susþin cã mortalitatea iatrogenã trebuie sã fie atent investigatã ºi cã terbuiesc luate mãsuri adecvate în vederea prevenirii ei. Cuvinte cheie: moartea neaºteptatã; boli mintale; prelungirea intervalului QT.

Psychiatric disorders are not usually thought as 'life threatening' as physically illnesses such cancer, heart diseases or AIDS are. Nevertheless mortality rates for mental hospital patients are five times the rate in general population of Europe and North America (1). This occurs from suicide, accidental death, and natural causes among those previously psychiatrically ill (2). Excluding suicides and accidental death, common in psychiatry, the mortality rate remains high. The highest rate is among those with organic psychotic conditions, especially dementia, but is raised for all psychiatric diagnoses (3) and paradoxically is greater for those aged under 40 (4). Among the psychiatrically ill there have been accounts of sudden death with no organic disease, and also of unexpected death from known physical illness. (5) People with mental illness are at greater risk of sudden death, with a 3–5 fold increase compared with the nonpsychiatric population (6, 7). The World Health Organization define sudden death as unexpected death either within one hour of symptom onset in the presence of witnesses or within 24 hours of the person having been observed alive and symptom free in the absence of witnesses (8). Although pre-existing heart disease may be present, the time and

mode of death are unexpected by definition (9). Psychiatric patients are vulnerable to sudden death, often with a negative autopsy (6). The causes are not always clear. Recent publication indicates increased risk of sudden death in users of typical and atypical antipsychotic drugs (10, 11). Patients with anorexia nervosa are another group with a predisposition to sudden death with no apparent anatomical cause. Long QT has been proposed as a factor in these cases (12). Sudden death may arise from complications of the mental illnesses or as a result of psychotropic medication.

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MENTAL ILLNESSES AND SUDDEN DEATH Anorexia nervosa Anorexia nervosa (AN) is a life-threatening condition, with significant risk of death due to its complications (13). It affects from 0.5 to 1% of young women and it has the highest mortality rate of all major mental disorders. 5% of the patients die in the first 4 years and 20% die within 20 years after diagnosis, many deaths occurring suddenly (14). The causes of death are very different in AN. Although the eating disorders, particularly AN have many

Resident in Psychiatry, Clinical Hospital of Psychiatry “Prof. Dr. Alexandru Obregia”, Bucharest, Romania, Contact e-mail: [email protected]

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medical complications it is unclear which are responsible for the increased mortality. Several pathological processes are likely to be involved. The most frequent cause of death is serious starvation with cachexia; this leads to both metabolic and cardiovascular collapse. Nutritional complications, electrolyte imbalance and dehydration may also be relevant. Other possible causes are potassium d e f i c i e n c y, s t r o k e , p u l m o n a r y e d e m a , bronchopneumonia, chronic bronchitis, emphysema, carcinoma, acute cardiac dysrhythmia, chronic inflammation and accidents. The suicide accounts for approximately 20–30% of the deaths (15-17). The most common methods of suicide are self poisoning, hanging, alcoholic poisoning and drowning (18). In 20 % of the deaths the cause cannot be identified (16). While suicide data usually are precise, most of all deaths resulted from inadequately defined complications of eating disorder, and in some cases the cause of death, including sudden death, is reported as unknown (17). AN is associated with a high rate of cardiac abnormalities, 86% of the patients showing electrocardiographic abnormalities, reduced left ventricular mass, the heart appearing small on X-ray, impaired myocardial performance, pericardial effusion, mitral regurgitation (19). Although some reports indicated an association between sudden death in individuals with anorexia nervosa and QT prolongation on routine electrocardiography, the incidence and the clinical consequences of such abnormalities remain controversial: some studies show no increasing QTc, while other studies show significant prolongation of QTc interval (14, 20). In addition, a common sign on ECG of AN patients is known to be bradycardia. The data from a meta-analysis showed that heart rate (HR) alteration began during the first year of the disease and with time returned to normal, probably due to compensatory mechanisms. QTc interval prolongation (within normal range) manifested itself later than bradycardia, and later in the course of the disease started to shorten. It is uncertain when exactly QT prolongation begins, and when the greatest risk for cardiac abnormalities occurs (14). The risk factors for acquired long QT syndrome include: (a) drugs that prolong repolarisation (QT interval); (b) electrolyte imbalance, particularly hypokalemia and hypomagnesemia; (c) bradycardia; (d) cardiac ischemia with reperfusion; (e) left ventricular dysfunction; (f) severe dieting; (g) acute central nervous system injury; and (h) congenital long QT syndrome. Many of them are common in AN. These risk factors can alter myocardial refractoriness, resulting in Torsade de Pointes arrhythmia and eventually in sudden death. (14, 21). In AN, starvation causes hypoglycemia which, may cause an acquired long QT syndrome, possibly through a direct effect of epinephrine, which regulates potassium, calcium, and chloride channels via cAMP (22). A genetic change in a protein that is responsible for the potassium transport during repolarisation, metabolic aberrations associated with malnutrition, dehydration, hypoglycemia or drugs could explain QT prolongation (17, 19). These assumptions are speculative but still could be well integrated into the concept of the condition of protein deficiency in anorexia nervosa. 106

In long QT syndrome, the most life threatening cardiac events are associated with physical or emotional stress, but deaths can occur even during the sleep. Physical stress introduced during low protein diet together with congenital long QT syndrome is likely to cause lifethreatening cardiac events in AN patients (23). AN is often associated with another psychiatric disorder such: depression, social phobia, and obsessivecompulsive disorder. The medical treatment for these disorders associated with AN, should be carefully chosen because many antidepressants and antipsychotics themselves tend to prolong QT interval. Thus it becomes difficult for clinicians to choose the right pharmacotherapy for these patients considering the pathophysiological changes of the disease (14, 23) . Patients with AN are seen usually by psychiatrists. They tend to deny their psychiatric and somatic symptoms. As the course of AN disease is commonly long it remains unclear how frequently AN patients should be sent by psychiatrists for somatic and especially cardiological investigations. Some patients may be cardiologically healthy when AN is diagnosed, other might have undetected cardiological abnormalities prior to the onset of AN. Cardiological abnormalities may also appear in the course of AN as a consequence of metabolic changes. It is unclear how these abnormalities vary in different time periods during the course of AN. A systematic ECG evaluation establishing the individual QTc variation and temporal changes in AN patients could be appropriate. If QTc prolongation is detected, even in the normal range, further cardiological examination for risk assessment and systematic clinical surveillance of the cardiovascular system should be considered. A model of clinical monitoring of the cardiovascular system for patients with AN should be elaborated. (14) Advances in treatment of the psychological aspects of the disease, better treatment of psychiatric comorbidities, as well as advances in the medical treatment with better refeeding strategies and better control of the medical complications, may account for the decrease in mortality from both natural and unnatural causes of death in AN (24). Drug use The common history of drug use in adults with undetermined causes of death has led to hypothesize that chronic drug abuse increases the risk of sudden death. It was reported the occurrence of myocardial ischemia in patients with a history of cocaine abuse who were shown to be free of cocaine at the time of ischemia by urine drug testing (25, 26). Drugs of abuse can cause or contribute to sudden death independent of their intoxicating properties. Cocaine causes hypertension, contraction band necrosis in myocardium, and acceleration of atherosclerosis. Coronary artery atherosclerosis, myocardial hypertrophy, focal necrosis of myocardium, and focal scarring of myocardium can all cause death and occur at the gross or microscopic level rather than at the molecular level. In undetermined death cases, these anatomical or microscopic findings (whether present as a result of drug abuse or not) are lacking to explain death. Cocaine is the most likely agent responsible for that risk in of sudden death in the patients with history of drug abuse (25).

Romanian Journal of Psychiatry, vol. XII, No.3, 2010 The blood concentration of cocaine does not correlate to clinical symptoms, nor with likelihood of death (26-28). Cocaine addicted patients recorded with a cardiac monitor after admission to a drug treatment facility, were found to have myocardial ischemia manifesting as episodes of ST elevation within the first few weeks of withdrawal when they were negative for cocaine and benzoylecgonine in both blood and urine (26). In human addicts, chronic cocaine use has been shown to alter endothelial cell function, rendering the addicts susceptible to ischemic vascular accidents by thrombosis of injured vessels, accelerated atherosclerosis, or by vasoconstriction and vasospasm (29). Chronic cocaine treatment administration on dogs has been shown to alter endothelial cell function the responsiveness of the left anterior descending coronary artery and the femoral artery to vasoactive substances, enhancing peripheral vasoconstriction and cardiac ischemia (30). Alcohol misuse The relationship between alcohol ingestion and sudden death is indisputable; what is controversial however, is its exact nature (31). Consumption of more than 5 drinks/ day is associated with an increased risk of sudden cardiac death. The risc appeared to be higher than 60% compared with occasional or light drinkers (32). High doses of alcohol use can lead to development of hypertension and cardiomyopathy , both of which increase the risk of sudden cardiac death. Moderate to high levels may directly influence cardiac electrophysiologic properties and increases the vulnerability to ventricular arrhythmias (33). A rapid rise in extracellular potassium, hypokalemia (less than 3.5 mM), and hypomagnesemia are associated with ventricular arrhythmias and sudden cardiac death in patients with structurally normal hearts. Hypomagnesemia is classically associated with polymorphic ventricular tachycardia or torsades de pointes. Hypokalemia with or without hypomagnesemia may be responsible for ventricular arrhythmias in subjects with hypertension and acute alcohol toxicity/withdrawal (34). Although alcohol consumption has potential adverse consequences on arrhythmogenesis, there are well-documented benefits of alcohol intake on atherogenesis and thrombosis. The results of some retrospective case-control studies have suggested that any a d v e r s e e ff e c t s t h a t a l c o h o l m a y h a v e o n arrhythmogenesis may be outweighed by favorable effects on atherogenesis and thrombosis. However, prospective studies have raised concerns that this may not be true (33). Most of the evidence suggests that light-tomoderate amounts of alcohol consumption (approximately 2-6 drinks/ week) shows no adverse effects related to the risk of sudden death. One study suggested that these modest levels of consumption may actually lower risk of sudden cardiac death. Therefore it appears that these levels of alcohol intake are most likely safe and could be beneficial. Modest alcohol intake is apparently safer with respect to sudden cardiac death compared with intermittent binge drinking given the association of the latter pattern with arrhythmias (33, 35). Despite the possible benefits of low levels of alcohol

consumption, there may be a fine line between benefit and risk. The increase in consumption to 2 or more drinks per day shows no apparent benefit on sudden death risk and heavier alcohol consumption definitely increases the risk (33). Guidelines for management of patients with ventricular tachycardia recommend: „Class I: 1. Complete abstinence from alcohol is recommended in cases where there is a suspected correlation between alcohol intake and ventricular arrhythmias. (Level of Evidence: C)” (34) S U D D E N D E AT H A N D P S Y C H O T R O P I C MEDICATION A variety of psychotropic drugs, particularly antipsychotic agents and tricyclic antidepressants are associated with sudden death (36). Inducing cardiac arrhythmias are one of the most likely mechanisms of sudden death because of electric membrane alterations induced by psychotropic drugs, resulting in electrocardiogram changes (37, 38). Psychotropic medication is not necessarily causative for excess mortality in psychiatric patients as higher doses might be linked with mortality through a contradictory factor such as worse physical condition in people with more serious mental health problems. Compared with the of non-suicide mortality, the number of deaths that might be attributable to medication is small, but according to most researchers, iatrogenic mortality must be taken seriously, with appropriate steps taken towards prevention (39). Antipsychotics Sudden unexplained death has been associated with antipsychotic drugs since their discovery but no consensus has been achieved on its frequency (40). Lately it has been expressed concerns about a relationship between antipsychotics and the risk of sudden cardiac death. Cardiovascular causes are most common, accounting for sudden and unexpected deaths. Most cases have no clear explanation on post-mortem examination and are thought to result from fatal arrhythmias. Currently, research into the carditoxic effects of antipsychotics is focused on molecular biology as well as in epidemiological approaches in order to explain both mechanism and clinical relevance of sudden death as a complication of psychiatric treatment (41, 42). A feasible mechanism by which antipsychotics may increase the risk of sudden death is drug-induced arrhythmia. Some antipsychotic drugs are associated with QT interval prolongation on electrocardiogram (40). The QT interval on the electrocardiograph is the time from the onset of ventricular depolarization to completion of repolarization. Prolongation of the QT interval is associated with an increased risk of dysrhythmia. QT interval varies with heart rate, becoming shorter as heart rate increases. Various correction factors have been proposed. The most frequently used is Bazett's correction (QTc = QT /√R–R). QTc prolongation is defined as QTc values above 450 ms (men) or 470 ms (women) (43, 44). Psychotropic drugs can affect the QT interval by blocking ion channels and slowing depolarisation. Slow depolarisation leads to the extention of the QRS interval, prolonging the QT interval. Drugs that block sodium 107

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channels in depolarisation induce mild modest of the QRS complex and are not thought to be associated with sudden death in individuals without preexisting cardiac disease. Repolarisation, on the other hand, involves sodium, calcium and potassium. The delayed rectifier channel for potassium (Ikr) is the channel most often involved in druginduced QT abnormalities. It is encoded by the human ether-a-go-go related gene (HERG). Drugs that block Ikr channels can slow repolarisation leading to the prolongation of the S–T segment and the T-wave, and subsequently of the QTc interval. Consequently these drugs can induce torsade de pointes and sudden death in apparently healthy adults (42, 45, 46). In vitro studies have been shown that clozapine, haloperidol, pimozide, sertindole and thioridazine block Ikr channels repolarisation (47); thioridazine and pimozide inhibit calcium channels; haloperidol and chlorpromazine block sodium conduction (48); chlorpromazine and thioridazine induced early 'after depolarisation', a trigger for torsade de pointes (49, 50); haloperidol, risperidone, sertindole, clozapine and olanzapine produce a dose-dependent prolongation of the QT interval (50). Some patient related factors influence the length of QT interval. QT interval increases with age (51). Women have a longer average QT than men (52), and a disproportionate number of drug-induced Torsade de Pointes occur in women (53). A number of clinical conditions are associated with increased risk of developing Torsade de Pointes: liver disease, renal disease, hypotiroidism, electrolytes abnormalities (hypokalaemia, hypomagnesemia, hypocalcaemia), CNS conditions (intracranial haemorrhage, stroke), cardiac conditions (congenital long QT syndrom, ischemic heart disease, dilated c a r d i o m y o p a t h y, h y p e r t r o p h i c o b s t r u c t i v e cardiomyopathy, left ventricular dysfunction, myocarditis, ventricular arrhythmias, hypertension, bradycardia, S-A or A-V block), drugs (diuretics possibly related to resulting electrolyte disturbance, concomitant imidazole/macrolide), etc (54) . Medical comorbidity and risk factors like, obesity, lack of exercise and diabetes have a considerable impact on accelerated mortality and no doubt influence the risk of sudden cardiac death. Obesity, hyperlipidemia and glucose intolerance may be exacerbated by antipsychotic drug therapy (55). The risk of the arrhythmia may be increased in patients with chronic alcohol misuse as this may be associated with liver disease which increases the risk of sudden death (56). Smoking is also an important risk factor, and the effects of smoking may be mediated by an increase in platelet adhesiveness and release of cathecholamines (57). The risk of sudden collapse is raised when antipsychotic medications are given during a period of high physiological arousal (58). Haloperidol, quetiapine, risperidone, chlorpromazine and trifluoperazine have a tendency to extend the QT interval even at therapeutic doses, but their link with sudden cardiac death is not yet clarified. Amisulpride, sulpiride, aripiprazole, olanzapine and zotepine have not been linked with an elevated risk of sudden cardiac death or QTc prolongation. In terms of sudden cardiac death these appear to be lower-risk antipsychotics(39). A consistent risk factor is the 108

cumulative dose of antipsychotic (including polypharmacy) (59). Although there have been a few reports of sudden death after the emergency use of psychotropic medication for rapid tranquillization, no deaths or serious cardiovascular events have been recorded during several recent large trials involving the treatment of over 1500 patients with ziprasidone v. haloperidol, olanzapine v. haloperidol or midazolam v. haloperidol–promethazine mix (42, 60, 61). The mechanism of sudden death following rapid tranquillisation appears to involve inadvertent suffocation rather than a drug-related effect (62). The response of a patient to a drug is very individual and therefore an individualized system of drug administration and monitoring needs to be developed which takes into account baseline QTc duration and its changes after a drug is introduced. A systematic approach stratifying psychiatric patients as those with short QTc (QTc ≤410 ms sec, not likely to develop proarrhythmia), borderline QTc (QTc = 420-440 sec, very low risk of proarrhythmia,), andprolonged QTc (≥450 sec, likely to develop proarrhythmia) has been proposed to improve the safety of administering antipsychotic drugs and to decrease the risk of drug-related sudden death in psychiatric patients (63). A strategy to prevent serious cardiac events has been proposed. A careful history would help elucidate any pre-existing cardiac disease, including heart failure, myocarditis, myocardial infarction and cardiac arrhythmias. A history of severe hepatic or renal impairment, eating disorder or any metabolic condition should be noted, as should significant alcohol or substance misuse. A detailed history of both psychotropic and nonpsychotropic drug use would allow clarification of possible pharmacodynamic and pharmacokinetic interactions are risk factors for significant prolongation of the QTc interval. It was suggested that patients about to receive higher-risk antipsychotics or those known to have vulnerability should have a baseline electrocardiogram before the treatment is started If significant QTc interval prolongations evident, serum electrolyte and magnesium levels should be measured. A cardiologist's opinion should be obtained if the patient reports recent cardiac ischaemia or significant abnormalities are suspected on an ECG (39). Antidepressants Tricyclic antidepressants (TCAs) in doses of less than 100 mg amitriptyline equivalents did not increase the risk of sudden cardiac death. Higher doses were associated with increased relative risk, particularly in patients with an elevated baseline risk of sudden death (64). The depression treatment might elevate the risk of ventricular arrhythmias. An elevated risk of sudden cardiac death is associated with antidepressants (65). Possible mechanisms for the elevated risk of ventricular arrhythmias and sudden cardiac death associated with depression include greater sympathetic nervous system activation (66), higher resting heart rates and increases in QT dispersion (67).The Brugada pattern, caused by genetic defects in sodium channels and associated with sudden death, has been described in patients taking TCAs in therapeutic doses as well as with overdose (68) .

Romanian Journal of Psychiatry, vol. XII, No.3, 2010 TCAs block phase 3 repolarization in His-Purkinje myocytes, leading to QTc prolongation on ECG. Specifically, TCAs inhibit outward potassium current by blocking potassium channels in phase 3, which ultimately results in prolongation of the QTc interval. QTc lengthening usually predisposes to the development of Torsades de Pointes that is favored by this bradycardia. Since TCAs by their anticholinergic effects cause tachycardia, torsades de pointes is less frequent (69). In a research were compared the median QTc intervals of the five SSRIs. The results showed significant differences. Citalopram was individually different to fluvoxamine, paroxetine and sertraline . This study showed that SSRIs are relatively safe in overdose. The exception was citalopram, which was significantly associated with QTc prolongation. Cardiac monitoring was recommended for patients treated with citalopram overdose and patients with associated cardiac disease (70). A few cases suggested that venlafaxine is a possible sinus bradycardia, first-degree atrioventricular block, bundle branch block, and even sudden death being reported (71). A recent large study has highlighted that use of venlafaxine was not associated with an excess risk of sudden cardiac death or near death compared with fluoxetine, or citalopram, in patients with depression or anxiety (72). Stimulant medications In recent years, concerns have arisen that stimulants may be associated with an increased risk of death. Such an association is biologically plausible given the central and peripheral catecholaminergic effects of stimulants and significant increases in heart rate and blood pressure that accompany their use (73). Using the Adverse Event Reporting System, FDA (The Food and Drug Administration) reported 11 sudden deaths in pediatric patients taking methylphenidate from January 1992 to February 2005 (74). One recent study has reported a significant association or “signal” between sudden unexplained death and the use of stimulant medication, specifically methylphenidate. While the data have limitations that preclude a definitive conclusion, its findings draw attention to the potential risks of stimulant medications for children and adolescents, which warrant clinical attention and further study. No significant differences in gender or race between the sudden unexplained deaths were reported (75). In 2008, the American Heart Association recommended considering routine ECGs prior to starting children with ADHD on stimulant and other psychotropic therapy regimens (76). Despite rare the phenomenon of sudden death in mental illness requires enough attention for its prevention. The ideal solution would be to prevent the processes that cause sudden death and, strategies aimed to identify the persons at particularly high risk of sudden death represents a major challenge. In particular, psychiatrists, together with general practitioners, should pay more attention to prevention, assessment, early diagnosis, and treatment of their patients' somatic diseases. Improvements in this area require better integration between different components of the health system.

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Alina Beldie: Sudden Death In Psychiatric Disorders

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