Academic Department of Psychiatry, University of Newcastle upon Tyne
Wolfson Unit of Clinical Pharmacology, University of Newcastle upon Tyne
Academic Department of Psychiatry, University of Newcastle upon Tyne
Wolfson Unit of Clinical Pharmacology, University of Newcastle upon Tyne
Correspondence: Dr S. H. L. Thomas, Wolfson Unit of Clinical Pharmacology, University of Newcastle, Newcastle NE2 4HH, UK. Tel: 0191 222 8094; fax: 0191 261 5733; e-mail: simon.thomas{at}ncl.ac.uk
See editorial, pp.
483484, this issue.
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ABSTRACT |
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Aims To assess the risk of sudden unexplained death associated with antipsychotic drug therapy and its relation to drug dose and individual agents.
Method A casecontrol study of psychiatric in-patients dying suddenly in five hospitals in the north-east of England and surviving controls matched for age, gender and mental disorder. Logistic regression analysis was used to identify significant risk factors, and odds ratios were calculated.
Results Sixty-nine casecontrol clusters were identified. Probable sudden unexplained death was significantly associated with hypertension, ischaemic heart disease and current treatment with thioridazine (adjusted odds ratio=5.3, 95% CI 1.7-16.2, P=0.004). There was no significant association with other individual antipsychotic drugs.
Conclusions Thioridazine alone was associated with sudden unexplained death, the likely mechanism being druginduced arrythmia.
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INTRODUCTION |
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METHOD |
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Cases
All in-patient deaths involving those aged 18-74 years (inclusive) from 1
January 1984 to 31 December 1995 were identified and medical notes were sought
and screened. Death was classified as probable sudden
unexplained death provided that (a) the patient died within 1 h of being
observed in their usual state of health (or was found dead more than 1 h after
having last been seen, but having been seen in their usual state of health
within the previous 24 h) and (b) there was no evidence of a non-cardiac
cause, including choking or convulsions.
Patients could be included as cases if they had suffered recent symptoms potentially caused by prodromal cardiac arrhythmia (dizziness, palpitations, syncope, chest pain or breathlessness) provided that there was no clinical evidence of an alternative cause such as myocardial infarction, stroke or chest disease.
Post-mortem data were sought, including from the local coroner, for all cases of probable sudden unexplained death. If an alternative cause of death was demonstrated, including myocardial infarction, the patient was excluded as a case. If no alternative cause for death was identified, the death was classified as confirmed sudden unexplained death. Coronary artery disease did not exclude use as a case unless there was evidence of recent coronary thrombosis or recent myocardial infarction.
Notes of all cases were examined independently by a researcher who was blind to drug therapy, to confirm that study criteria for sudden unexplained death were met. Possible cases where there was disagreement were rejected.
Controls
Two controls were sought for each case. Both were in-patients at the same
hospital at the time of death of the case. They were each matched for age,
gender and duration of in-patient stay and one was also matched for primary
psychiatric diagnosis. The purpose of using two controls was to increase the
statistical power of the study. The availability of a control unmatched for
psychiatric diagnosis allows the investigation of diagnosis as a risk for
sudden death, whereas the availability of a control matched for psychiatric
diagnosis is helpful if diagnosis is found to be a significant factor for
sudden cardiac death. The use of two types of controls also allows the
consistency and robustness of associations with drug therapy to be determined
in different models. Controls were identified by searching hospital databases
for patients of the same gender who were within 5 years of the age of the
case. For cases who had been in hospital less than 5 years, controls were
sought from the age- and gendermatched controls admitted within 1 year of the
death of the case. Close matching by year of admission was more difficult for
cases who had been in hospital for more than 5 years. For these, age- and
gendermatched controls who had also been in hospital for more than 5 years and
who were in-patients at the time of death of the case were sought. For either
group, the potential controls selected were those whose date of admission most
closely matched that of the case. If no controls were identified, the process
was repeated using a 10-year age band. The same process was used to select the
second controls, who were also matched according to primary psychiatric
diagnosis and classified according to ICD-10
(World Health Organization,
1992) in one of five categories (organic disorders, schizophrenia,
affective disorders, alcohol dependence or misuse and other,
including neuroses, eating disorders and personality disorders).
Data collected
Psychiatric diagnoses, medical history, cardiac history and all drug
therapy within the previous 6 months prior to death (cases) or the index date
(controls) were recorded for both patients and controls. For controls of those
cases who had died within 60 days of admission, the index date was defined as
the same number of days after admission as death occurred in the case. If the
interval was longer, the index date was taken as the date of death of the
case. The index time was the time of death of the case. Exposure to drugs was
defined as use, according to the hospital prescription chart, within 24 h of
death or the index date and time. Antipsychotic drugs were put in three groups
by dose using the following chlorpromazine equivalent dose ranges: zero
(none), 1000 mg per day (low dose) and > 1000 mg per day (high
dose).
Statistical analysis
Probable sudden death and confirmed sudden death were defined as the
outcome variables for separate conditional logistic regression analyses. The
statistical software packages SPSS version 10 and EGRET for Windows (1999,
Cytel Software Corporation, Cambridge, Massachusetts, USA) were used.
The original design specified the matching of each case with two controls, one of which was matched for psychiatric disease group. Before performing this analysis, a 1:1 casecontrol analysis was to be performed using the single control unmatched for psychiatric disease to determine if there was an association between psychiatric disease group and sudden cardiac death. If this was found, the influence of psychiatric disease would be included in the final model. In the absence of a significant association, it was to be ignored.
For each analysis, unadjusted odds ratios for probable sudden unexplained death were first calculated for a range of possible predictive variables, including specific drug therapy and cardiac disease. Adjusted odds ratios were then obtained via the conditional logistic regression model, incorporating those variables where P<0.05. The method of backward stepwise regression was also used to establish the most important predictive variables, for which adjusted odds ratios were calculated. Using this method, the least significant predictive factors are eliminated from the conditional logistic regression analysis in turn, until only those that are significantly associated with sudden death remain. Variables were retained in the model if their significance level was less than 15%. The unadjusted and adjusted odds ratios using confirmed sudden death as the outcome variable were obtained using the same approach.
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RESULTS |
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Of the 74 probable cases, 37 (50%) were female. The median age was 69 years. Seventeen cases were younger than 65 years but only one was less than 50 years old. No sudden deaths occurred during restraint or within 1 h of parenteral antipsychotic medication. Adequately matched controls could not be found for 5 (disease unmatched) and 11 (disease matched) probable cases, leaving a total of 69 and 63 clusters for the respective casecontrol analyses. Demographic information and breakdown by principal psychiatric diagnosis, cardiovascular disorder and drug therapy are shown in Table 1. There was a particular lack of information on smoking and alcohol use in the medical notes.
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Two initial analyses were performed using single controls, unmatched and matched for psychiatric diagnosis, respectively. Table 1 shows the unadjusted odds ratios for the probable sudden death group (n=69) using the single control unmatched for diagnosis. Odds ratios adjusted using conditional logistic regression and backwards stepwise regression are shown in Table 2. In this analysis, the psychiatric conditions of mood disorder and schizophrenia were not significantly associated with sudden cardiac death. However, the presence of organic disorder was significantly associated after adjustment for confounding. Other factors significantly associated with probable sudden death in this analysis were the presence of a history of hypertension or myocardial infarction and current treatment with diuretics or thioridazine. There was a significant negative association with carbamazepine and sodium valproate therapy (Table 2).
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Because of the significant association between organic disease and sudden death, a further casecontrol analysis was performed using the single control matched for psychiatric disorder. In this analysis (data not shown), factors significantly associated with sudden death after adjustment for confounding using backwards stepwise regression were the presence of ischaemic heart disease (odds ratio=17.0, 95% CI 2.3 to >100, P=0.005) or hypertension (odds ratio=13.6, 95% CI 1.6 to >100, P=0.018), and current therapy with thioridazine (odds ratio=15.4, 95% CI 2.6-89.5, P=0.002). In this analysis, there was no significant association with diuretic therapy.
The prespecified primary analysis for the study used both controls to optimise study power. Because the presence of organic disorder was shown to be significantly associated with sudden unexpected death, this was adjusted for in the model. In this analysis, sudden unexpected death was again significantly associated only with hypertension, ischaemic heart disease and thioridazine therapy (Table 3). The possibility was considered that differences in the duration of hospital stay between cases and controls might be an important confounding factor, leading to a spurious association between thioridazine therapy and sudden death. However, the use of thioridazine was not related to duration of hospital stay, and removing those clusters with the poorest matching by duration of hospital stay from the analysis did not alter the size or statistical significance of the odds ratio linking thioridazine with sudden death.
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To examine for the presence of a doseresponse relationship with sudden death, further analyses were performed grouping antipsychotic drugs together, according to dose in chlorpromazine equivalents. When both controls were used in the analysis, a significant relationship between high-dose antipsychotic therapy and sudden death was obtained by conditional logistic regression (low-dose odds ratio=1.6, 95% CI 0.7-4.1, P=0.28; high-dose odds ratio=12.5, 95% CI 1.1-139.2, P=0.04). However, the odds ratio for high-dose therapy was not statistically significant at the 5% level after backwards stepwise regression (odds ratio=7.8, 95% CI 0.8-71.3, P=0.07) or if the single psychiatric disease-matched controls were used (adjusted odds ratio=19.7, 95% CI 0.72 to > 100, P=0.08).
To study a potential doseresponse in the relationship between
thioridazine and sudden death, an analysis was performed examining the effects
of low- and high-dose thioridazine exposure. No cases were prescribed
thioridazine at doses above 1000 mg (the chlorpromazine equivalent threshold
for high dose) or 800 mg per day (maximum recommended by the British
National Formulary (British Medical
Association & Royal Pharmaceutical Society of Great Britain,
2000)). The median dose of 75 mg per day was chosen as a threshold
for the high dose. Both low- (75 mg/24 h) and high-dose (>75 mg/24 h)
thioridazine exposure were each significantly associated with sudden death and
these effects were consistent whether either or both controls were used
(Table 4). However, no
statistically significant doseresponse effect could be
demonstrated.
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A casecontrol analysis was also performed using the same methods by restricting analysis to the subgroup of cases with confirmed sudden death (n=27). Using both controls, only ischaemic heart disease was significantly associated with sudden death. Thioridazine was not a statistically significant predictor of confirmed sudden death, but the odds ratio for the association was greater than unity and the power of this part of the study is low (Table 5).
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DISCUSSION |
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Characteristics of sudden death patients
This study indicates that most patients who die suddenly without
explanation in psychiatric hospitals are over 50 years old and many have
pre-existing cardiovascular disease, in common with those at greatest risk in
the wider community. No cases occurred in the aftermath of parenteral
administration of antipsychotics or in the context of restraint, and this is
consistent with the findings of other systematic research
(Ungvari, 1980;
Davis & Zhang, 1988). The
prominence of these factors in previous studies involving younger patients
(Jusic & Lader, 1994; Lareya, 1995) may result from
reporting bias. However, it is possible that antipsychotic drug-induced deaths
that involve younger people occur more often in the community than in hospital
and such deaths would not have been detected in this study. The low
post-mortem rate suggests that many of the deaths in this study were not
suspected by clinicians to be drug-related.
Study limitations and strengths
This matched casecontrol study has a number of limitations. The
retrospective nature of the study and the reliance on descriptions of death
recorded in medical notes are disadvantages. Records are often incomplete for
important risk factors such as underlying cardiac disease, smoking or use of
alcohol or illicit drugs. The low post-mortem rate raises the possibility that
some of the deaths were from causes other than cardiac arrythmia, although
these were only found in 3 out of 30 cases when a post-mortem had been done.
Strengths of the study design and setting include the systematic method for
collecting cases, which minimises potential recall or reporting bias, and the
examination of hospital drug charts, which allows the collection of more
detailed and accurate information about drug use than would be possible in a
community setting.
Factors associated with sudden death
In this study, sudden unexplained death in psychiatric in-patients was
associated with ischaemic heart disease, previous arrythmia and hypertension.
Diuretic therapy was a significant risk factor in one analysis but not others.
This might be because it is a marker for underlying cardiovascular disease or
because diuretic therapy itself increases the arrythmia risk by causing
hypokalaemia, as reported previously
(Siscovick et al,
1996).
Thioridazine was the only single antipsychotic drug therapy found to be an independent risk factor for sudden unexplained death. There was also a possible association with increasing total antipsychotic dose. Droperidol has previously been shown to be associated with repolarisation abnormalities (Reilly et al, 2000), but there were too few exposed cases in this study to perform a reliable analysis of the impact of this drug on sudden death. Tricyclic antidepressants prolong cardiac repolarisation and have been associated with sudden death (Coull et al, 1970; Ballinger & Ramsay, 1976). However, no association was found in this study. The apparent negative association between sudden unexpected death and the antiepileptic drugs carbamazepine and sodium valproate, may be due to diagnostic bias because deaths possibly caused by epilepsy were excluded as cases. However, we cannot exclude the possibility that these drugs may afford some protection by an unknown mechanism.
Confounding factors
In spite of the small size of this study and its retrospective nature, we
have shown a consistent association between thioridazine and
probable sudden death. The possibility should be considered that
this association is not causal but results from confounding or bias. Age is
unlikely to provide important confounding because cases and controls were
matched for age, albeit in 5- or 10-year bands, and the mean ages of cases and
controls were similar. It seems unlikely that thioridazine would be used
preferentially in patients with cardiac disease and there is no evidence of
this; indeed, adjustment for the influence of cardiovascular disease increases
the strength of the association. A cohort effect on prescribing linked to
length of stay in hospital is also unlikely because length of stay was matched
for patients dying within 60 days. Although there were differences in the
cases and controls for mean length of stay when the case died after more than
60 days, removal of those clusters with the poorest matching did not affect
the strength of the association between sudden death and thioridazine. We
cannot completely exclude the possibility that thioridazine use is a marker
for a more debilitated population more prone to sudden death for other
reasons. It has not been possible to correct for the possible confounding
effects of smoking or use of alcohol or illicit drugs, because information on
these factors was usually missing from the patient's notes. If these factors
contribute to the increased risk of sudden death associated with thioridazine,
this would mean that thioridazine must be prescribed preferentially to
smokers, drinkers or illicit drug-takers, which seems implausible. Caution is
also required because no significant association was found between post-mortem
confirmed sudden unexplained death and thioridazine therapy, and
neither was a doseresponse relationship demonstrated. However, the
small numbers of cases and controls involved hinder both of these
analyses.
Mechanism of sudden death
Although other mechanisms of antipsychotic-induced sudden death have been
suggested, including convulsions, hypotension, choking or asphyxia,
myocarditis or pulmonary embolism, we believe that the most likely explanation
for the association demonstrated here is that thioridazine causes arrythmias
and sudden cardiac death. This finding is consistent with other evidence.
Although most antipsychotic drugs show some propensity for cardiac adverse
effects, thioridazine is cited most frequently. It appears more cardiotoxic
than other antipsychotic drugs in overdose
(Buckley et al, 1995) and prolongs the heart rate corrected QT interval to a greater extent
(Reilly et al, 2000).
Thioridazine is a potent blocker of the delayed rectifier potassium channel
(Ikr), the main determinant of cardiac repolarisation
(Drolet et al, 1999). This effect is likely to be independent of the drug's dopamine receptor
blocking effect because it occurs with antipsychotic drugs such as sertindole
that have low potency for dopamine receptors, as well as with a wide range of
drugs that do not block dopamine receptors
(Thomas, 1994). Torsades de
pointes induced by thioridazine has been reported frequently in the context of
both overdose (Kiriike et al,
1987) and therapeutic administration
(Denvir et al, 1998).
A previous study linked sudden death with thioridazine, although this did not
adjust for age (Mehtonen et al,
1991).
Clinical implications
Although rarely prescribed now as a first-line drug for schizophrenia,
thioridazine is often perceived as having fewer adverse effects than more
potent neuroleptics and, until recently, was commonly prescribed for anxiety,
confusion and behavioural problems. Considering the risk of repolarisation
abnormalities and the apparent association with sudden cardiac death, this
widespread use of thioridazine can no longer be justified. If thioridazine is
used at all, it should be given in the lowest possible dose because higher
doses have been shown to cause more marked repolarisation abnormalities.
However, we were unable to demonstrate a doseresponse effect in this
study and low doses are not free from risk. Based on accumulating evidence of
cardiotoxicity, regulatory authorities in the USA and the UK have now
recommended restriction of thioridazine prescribing to those with
treatment-resistant schizophrenia. Caution is advised where thioridazine is
prescribed to patients with cardiovascular diseases and is contraindicated in
those most at risk of torsades de pointes. Electrocardiographic screening
prior to initiation of drug therapy and monitoring during therapy are
recommended. Co-prescription with inhibitors of CYP2D6 a hepatic
cytochrome P-450 isoform responsible for thioridazine metabolism
should be avoided, and patients should be monitored for hypokalaemia, which
can also increase the risk of arrhythmia
(Committee on Safety of Medicines,
2001).
The results of this study should be interpreted with caution. We cannot be reassured that significant risks do not exist with other antipsychotic drugs. Larger studies of sudden unexplained death in psychiatric in-patients are needed, such as the national study now underway (Appleby et al, 2000).
Sudden unexplained death in psychiatric patients is uncommon. A proportion may be related to antipsychotic drug therapy, particularly thioridazine, and a higher index of suspicion is required when deaths occur, whether in hospital or in the community. This is a rare adverse drug reaction that should be considered in the context of the major benefits offered to patients by appropriate antipsychotic therapy.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Received for publication . Revision received November 20, 2001. Accepted for publication February 11, 2002.
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