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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.
11
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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Alina Beldie: Sudden Death In Psychiatric Disorders
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
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Alina Beldie: Sudden Death In Psychiatric Disorders
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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