## Abstract

Aims

Psychotropic medication increases cardiac mortality, but the reasons for this association are not clear. We studied the role of psychotropic drugs as a triggering factor of sudden cardiac death (SCD) during an acute coronary event.

Methods and results

The use of medication was compared between victims of SCD and survivors of an acute coronary event in a case–control study including a consecutive series of victims of SCD (n= 1814, mean age 65 ± 11 years) verified to be due to an acute coronary event at medico-legal autopsy and consecutive series of patients surviving an acute myocardial infarction (AMI; n= 1171, mean age 66 ± 12 years). The medication history was obtained from autopsy/hospital records and interviews with relatives of SCD victims and AMI patients. The use of antipsychotics [9.7 vs. 2.4%, odds ratio (OR) 4.4, 95% confidence interval (CI) 2.9–6.6; P< 0.001] and antidepressants (8.6 vs. 5.5%, OR: 1.6, 95% CI: 1.2–2.2; P= 0.003) was more common in the SCD than AMI group, but the use of benzodiazepines did not differ between the groups (11.7 vs. 13.2%; P= 0.270). The use of antipsychotics remained as a significant risk factor for SCD after adjustment for confounding variables (OR: 3.4, 95% CI: 1.8–6.5; P< 0.001). Combined use of phenothiazines and any antidepressant was associated with a very high risk of SCD (OR: 18.3, 95% CI: 2.5–135.3; P< 0.001).

Conclusion

The use of psychotropic drugs, especially combined use of antipsychotic and antidepressant drugs, is strongly associated with an increased risk of SCD at the time of an acute coronary event.

## Introduction

Sudden cardiac death (SCD) accounts for one out of every two deaths from cardiovascular diseases.1 An acute coronary event has been considered to be the most common pathophysiological mechanism leading to SCD.1 Prevention of SCD caused by an acute coronary event has remained a challenge for clinicians, because recognizable risk factors for SCD appear to be partly the same as those predisposing to a non-fatal coronary event. In fact, there is relatively little information available on possible differences in risk profiles between the subjects who survive and those who die suddenly during an acute coronary event.2

Mental disorders have been associated with an increased risk of cardiovascular mortality.3–7 Recently, depression has been shown to predict specifically the occurrence of SCD.8–11 In addition, there is growing evidence that also the psychotropic drugs used to treat psychiatric disorders could increase the risk of SCD.11–14 Despite the epidemiological evidence of an association between depression, anxiety, and increased risk of cardiovascular mortality, the exact pathways, and pathophysiological mechanisms of these associations are not well established. It is not known, if either the mental disorders or the psychotropic drugs used to treat them predispose to the occurrence of an acute coronary event or if they increase the vulnerability to a fatal outcome during such an event.

A prospective case–control study, the Finnish Genetic Study of Arrhythmic Events (FinGesture)15 was designed to compare genetic and other risk profiles of the victims of SCD with the survivors of an acute coronary event. In this study, we have compared the medications being used by these groups. Our primary focus was to study possible differences in the use of psychotropic drugs between the subjects who died suddenly and those who survived an acute ischaemic event.

## Methods

### Study populations

The FinGesture study was started in 1998 and by the end of 2009 it had gathered data on 2732 consecutive victims of out-of-hospital sudden death from a defined geographical area, i.e. Oulu University Hospital District in northern Finland. All the victims of sudden death were autopsied in the Department of Forensic Medicine, University of Oulu, Finland. Sudden cardiac death caused by an acute coronary event has been previously defined in detail.2,15,16 In each case of sudden death, the mechanism of death was clarified and all patients who were considered to have died due to any cause other than SCD during an acute coronary event were excluded from the study. With respect to out-of-hospital SCD victims, those with (i) a witnessed sudden death within 6 h of the onset of symptoms or within 24 h of the time that the victim was last seen alive in a normal state of health and (ii) evidence of a coronary complication, defined as a fresh intracoronary thrombus, plaque rupture or erosion, intraplaque haemorrhage, or critical coronary stenosis (>75%) in the main coronary artery were included in the SCD group. Cases suggesting severe heart failure, e.g. those with massive myocardial necrosis (>50%) and signs of acute pulmonary oedema, and history of hospitalization due to congestive heart failure were not defined as ischaemic SCDs. Toxicologic investigations were made in cases of any suspicion of intoxication (60%), and cases with suicide were excluded. After exclusions, 2082 of 2732 victims of sudden death were defined as having died due to an acute coronary event.

Information about the victims' latest medications, including doses of psychotropic medications, was collected from the medico legal autopsy reports and from standardized questionnaires asked from the victims' closest relatives. If the information about medication was not described reliably in the autopsy report or questionnaires, the case was excluded (n= 268). After these exclusions, a total of 1814 SCD cases were included in the study. Information about the prior medical history was obtained from a combination of the available electronic medical records, existing from 1995 in the area of present patient population, and from standardized questionnaires asked from the victims' closest relatives as described earlier.16

The control group consisted of survivors of AMI, collected between 1996 and 2004 (n= 1256) at the Department of Internal Medicine, University Hospital of Oulu.17,18 This sample included all AMI patients from those periods from the same geographical area from which the SCD victims were gathered. Survivors of AMI were recruited to participate during the first 7 days after the diagnosis of AMI, which was confirmed by using the contemporary guidelines.17,18 Information about the patients' medications and prior cardiovascular history was obtained from the medical records during their hospital stay. If no reliable information about medication was available, the patient was excluded from the study (n= 55). Additional 30 patients were excluded, who experienced AMI at the post-operative phase after surgery. The qualifying diagnostic criteria of the patients have been described in detail elsewhere.17,18 Forty-two per cent of the patients had ST-segment elevation AMI and 58% had non-ST elevation AMI. Acute myocardial infarction was anterior in 45% of patients, inferior in 41%, and some other location in 14% of the patients. A total number of 1171 AMI patients were included in the study.

Antipsychotic drugs were grouped as typical, first generation, antipsychotics, including phenothiazines, thioxanthenes, butyrophenones, and benzamides, and atypical, second generation antipsychotics, including aripiprazole, clozapine, risperidone, quetiapine, olanzapine, and drugs similar to these agents. Antidepressants were categorized into three groups; tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and other antidepressants, including venlaflaxine, mianserin, mirtazapine, and drugs similar to these agents. The doses of used antipsychotic and antidepressant drugs were categorized as (i) low dose, (ii) normal or intermediate dose, and (iii) high dose according to previously reported recommendations.19–21 Circadian rhythm of SCD was also compared between those using and not using psychotropic drugs.

The study conforms to the principles outlined in the Declaration of Helsinki and the study protocol was approved by the Ethics Committee of The Northern Ostrobothnia Hospital District. All living subjects had an opportunity to refuse to participate and gave written informed consent.

### Statistical analysis

Differences in continuous clinical variables between study groups were tested with a two-sided t-test. Normal distribution of data was confirmed by using the Kolmogorov–Smirnov test. Differences in categorical characteristics between study groups were tested using a χ2 test. Logistic regression analysis was used to assess the risk of SCD related to different psychotropic medications after adjustment for demographic risk factors, such as male gender, a history of angina pectoris, hypertension, diabetes, a history of prior AMI, hypercholesterolaemia, and the use of cardiovascular medications, i.e. lipid-lowering therapy, statins, nitroglycerin, acetosalicylic acid, β-blockers, Ca-channel blockers, diuretics, ACE-inhibitors or AT2-antagonists and flecainide, amiodarone or sotalol. All analyses were performed with the Statistical Package for Social Studies version 16.0 (SPSS, Inc., Chicago, IL, USA). P< 0.050 was considered significant.

## Results

### Patient characteristics

Demographic data and the common cardiac risk factors are presented in Table 1. The victims of SCD were more often males and current smokers, while a history of angina pectoris, hypertension, diabetes (type I or II), and hypercholesterolaemia were more common among survivors of AMI. A higher percentage of AMI survivors had a history of a prior myocardial infarction.

Table 1

Characteristics of the study populations

Characteristic SCD (n= 1814) AMI (n= 1171) P-value
Age, years 65.2 ± 11 65.5 ± 12 0.393
Sex, males 1449/1814 (79.9) 832/1171 (71.1) < 0.001
BMI 26.8 ± 5.2 27.6 ± 4.4 < 0.001
Smoking status   0.001
Never 102/292 (34.9) 315/945 (33.3)
Ex 66/292 (22.6) 316/945 (33.4)
Current 124/292 (42.5) 314/945 (33.2)
Hypercholesterolaemia 162/1681 (9.6) 721/1120 (64.4) <0.001
Diabetes type I or II 333/1720 (19.4) 299/1161 (25.8) <0.001
Hypertension 634/1665 (38.1) 631/1162 (54.3) <0.001
Angina pectoris 165/1670 (9.9) 590/1129 (52.3) <0.001
Prior AMI 184/1695 (10.9) 264/1153 (22.9) <0.001
Characteristic SCD (n= 1814) AMI (n= 1171) P-value
Age, years 65.2 ± 11 65.5 ± 12 0.393
Sex, males 1449/1814 (79.9) 832/1171 (71.1) < 0.001
BMI 26.8 ± 5.2 27.6 ± 4.4 < 0.001
Smoking status   0.001
Never 102/292 (34.9) 315/945 (33.3)
Ex 66/292 (22.6) 316/945 (33.4)
Current 124/292 (42.5) 314/945 (33.2)
Hypercholesterolaemia 162/1681 (9.6) 721/1120 (64.4) <0.001
Diabetes type I or II 333/1720 (19.4) 299/1161 (25.8) <0.001
Hypertension 634/1665 (38.1) 631/1162 (54.3) <0.001
Angina pectoris 165/1670 (9.9) 590/1129 (52.3) <0.001
Prior AMI 184/1695 (10.9) 264/1153 (22.9) <0.001

BMI, body mass index. Values are expressed as mean (SD) or number of subjects (%). Probability values refer to two-sided t-test, and χ2 test comparing victims of SCD to AMI patients.

### Medication

The medications being used by the study groups are presented in Table 2. The use of cardiovascular or antihypertensive medication was more common among AMI survivors. The use of any psychotropic medication, including benzodiazepines, antidepressants, and antipsychotics, was significantly more common in the SCD than in the AMI group. In particular, the use of antipsychotics (P< 0.001) and antidepressants (P= 0.003) was significantly more common in the victims of SCD. In the group of antipsychotics, the use of phenothiazines, thioxanthenes, butyrophenones, and newer atypical antipsychotics was more common in the victims of SCD compared with AMI survivors. In the subgroups of antidepressants, there was no significant difference between the groups in the use of SSRIs or newer types of antidepressants, but the use of TCAs was more common in the SCD group. There was no difference in the use of benzodiazepines between the victims of SCD and the survivors of AMI (P= 0.270). The combined use of antipsychotics and antidepressants was associated with an increased risk of SCD (P< 0.001). A very high risk of SCD was seen in those subjects who had been prescribed both phenothiazine and antidepressant medications (OR: 18.3, 95% CI: 2.47–135.3; P< 0.001) (Figure 1).

Table 2

Medications of the study populations

Medication SCD (n= 1814) AMI (n= 1171) P-value
Cardiovascular medication
Any cardiovascular or antihypertensive medication 1039/1648 (63.0) 814/1165 (69.9) <0.001
Lipid-lowering therapy, other than statins 207/1499 (13.8) 74/1125 (6.6) <0.001
Statin 189/1483 (12.7) 289/1124 (25.7) <0.001
Nitrate/nitroglycerin 355/1519 (23.4) 394/1138 (34.6) <0.001
ASA 323/1491 (21.7) 460/1144 (40.2) <0.001
β-Blocker 444/1493 (29.7) 552/1148 (48.1) <0.001
Ca-channel blocker 150/1490 (10.1) 216/1129 (19.1) <0.001
Diuretic 275/1491 (18.4) 326/1138 (28.6) <0.001
ACE inhibitor or AT2-antagonist 292/1489 (19.6) 330/1132 (29.2) <0.001
Warfarin 123/1504 (8.2) 97/1126 (8.6) 0.689
Flecainide/amiodarone/sotalol 15/1488 (1.0) 24/1120 (2.1) 0.018
Digoxin 81/1489 (5.4) 78/1129 (6.9) 0.119
Insulin 79/1495 (5.3) 105/1127 (9.3) <0.001
Metformin/sulphonylurea 140/1492 (9.4) 157/1135 (13.8) <0.001
Asthma or chronic obstructive pulmonary disease medication 163/1497 (10.9) 148/1129 (13.1) 0.081

Psychotropic medication
Any psychotropic medication 322/1506 (21.4) 199/1131 (17.6) 0.016
Antipsychotic 145/1492 (9.7) 27/1120 (2.4) <0.001
Phenothiazine 82/1490 (5.5) 8/1118 (0.7) <0.001
Thioxanthene 16/1490 (1.1) –/1117 0.001
Butyrophenone 26/1490 (1.7) 6/1118 (0.5) 0.006
Benzamide 1/1490 (0.1) 1/1117 (0.1) —
Atypical 40/1490 (2.7) 15/1117 (1.3) 0.018
Antidepressant 128/1492 (8.6) 62/1120 (5.5) 0.003
Tricyclic antidepressant 43/1490 (2.9) 19/1118 (1.7) 0.049
SSRI 53/1490 (3.6) 26/1117 (2.3) 0.070
Other 37/1490 (2.5) 19/1116 (1.7) 0.174
Benzodiazepine 175/1494 (11.7) 148/1125 (13.2) 0.267
Medication SCD (n= 1814) AMI (n= 1171) P-value
Cardiovascular medication
Any cardiovascular or antihypertensive medication 1039/1648 (63.0) 814/1165 (69.9) <0.001
Lipid-lowering therapy, other than statins 207/1499 (13.8) 74/1125 (6.6) <0.001
Statin 189/1483 (12.7) 289/1124 (25.7) <0.001
Nitrate/nitroglycerin 355/1519 (23.4) 394/1138 (34.6) <0.001
ASA 323/1491 (21.7) 460/1144 (40.2) <0.001
β-Blocker 444/1493 (29.7) 552/1148 (48.1) <0.001
Ca-channel blocker 150/1490 (10.1) 216/1129 (19.1) <0.001
Diuretic 275/1491 (18.4) 326/1138 (28.6) <0.001
ACE inhibitor or AT2-antagonist 292/1489 (19.6) 330/1132 (29.2) <0.001
Warfarin 123/1504 (8.2) 97/1126 (8.6) 0.689
Flecainide/amiodarone/sotalol 15/1488 (1.0) 24/1120 (2.1) 0.018
Digoxin 81/1489 (5.4) 78/1129 (6.9) 0.119
Insulin 79/1495 (5.3) 105/1127 (9.3) <0.001
Metformin/sulphonylurea 140/1492 (9.4) 157/1135 (13.8) <0.001
Asthma or chronic obstructive pulmonary disease medication 163/1497 (10.9) 148/1129 (13.1) 0.081

Psychotropic medication
Any psychotropic medication 322/1506 (21.4) 199/1131 (17.6) 0.016
Antipsychotic 145/1492 (9.7) 27/1120 (2.4) <0.001
Phenothiazine 82/1490 (5.5) 8/1118 (0.7) <0.001
Thioxanthene 16/1490 (1.1) –/1117 0.001
Butyrophenone 26/1490 (1.7) 6/1118 (0.5) 0.006
Benzamide 1/1490 (0.1) 1/1117 (0.1) —
Atypical 40/1490 (2.7) 15/1117 (1.3) 0.018
Antidepressant 128/1492 (8.6) 62/1120 (5.5) 0.003
Tricyclic antidepressant 43/1490 (2.9) 19/1118 (1.7) 0.049
SSRI 53/1490 (3.6) 26/1117 (2.3) 0.070
Other 37/1490 (2.5) 19/1116 (1.7) 0.174
Benzodiazepine 175/1494 (11.7) 148/1125 (13.2) 0.267

Values are expressed as number of subjects (%). Probability values refer to χ2 test comparing victims of SCD to AMI patients.

Figure 1

Odds ratios of experiencing sudden cardiac death at the time of an acute coronary event in relation to use of psychotropic medications. The 95% confidence intervals are in parentheses and absolute numbers of patients are presented below the medication classes.

Figure 1

Odds ratios of experiencing sudden cardiac death at the time of an acute coronary event in relation to use of psychotropic medications. The 95% confidence intervals are in parentheses and absolute numbers of patients are presented below the medication classes.

### Risk analysis

The results of both univariate and multivariate analysis for potential SCD risk factors are summarized in Table 3. In the multivariate model, the use of antipsychotics remained as a significant risk factor for SCD after adjustment for demographic parameters (P< 0.001). In addition, the use of TCAs (P= 0.011), phenothiazines (P< 0.001), and butyrophenones (P= 0.037) remained as significant predictors of SCD. The combined use of phenothiazines and antidepressants (adjusted OR: 9.62, 95% CI: 1.15–80.8; P= 0.037) was strongly associated with an increased risk of SCD in the multivariate model.

Table 3

Univariate and multivariate analysis of the risk of sudden cardiac death

Characteristic Univariate

Multivariate

OR 95% CI

P-value
Lower Upper Lower Upper
Antipsychotics 4.36 2.87 6.62 <0.001 3.44 1.80 6.54 <0.001
Phenothiazines 8.08 3.89 16.8 <0.001 10.9 3.24 36.9 <0.001
Butyrophenones 3.29 1.35 8.02 0.006 6.74 1.12 40.6 0.037
Atypical antipsychotics 2.03 1.11 3.69 0.018 1.30 0.54 3.11 0.555
Antidepressants 1.60 1.17 2.19 0.003 1.37 0.85 2.21 0.191
Tricyclic antidepressants 1.72 1.0 2.97 0.049 3.41 1.33 8.77 0.011
SSRIs 1.55 0.96 2.49 0.07 1.03 0.52 2.06 0.925
Newer antidepressants 1.47 0.84 2.57 0.174 1.11 0.49 2.52 0.795
Benzodiazepines 0.88 0.69 1.11 0.267 1.04 0.71 1.53 0.843
Characteristic Univariate

Multivariate

OR 95% CI

P-value
Lower Upper Lower Upper
Antipsychotics 4.36 2.87 6.62 <0.001 3.44 1.80 6.54 <0.001
Phenothiazines 8.08 3.89 16.8 <0.001 10.9 3.24 36.9 <0.001
Butyrophenones 3.29 1.35 8.02 0.006 6.74 1.12 40.6 0.037
Atypical antipsychotics 2.03 1.11 3.69 0.018 1.30 0.54 3.11 0.555
Antidepressants 1.60 1.17 2.19 0.003 1.37 0.85 2.21 0.191
Tricyclic antidepressants 1.72 1.0 2.97 0.049 3.41 1.33 8.77 0.011
SSRIs 1.55 0.96 2.49 0.07 1.03 0.52 2.06 0.925
Newer antidepressants 1.47 0.84 2.57 0.174 1.11 0.49 2.52 0.795
Benzodiazepines 0.88 0.69 1.11 0.267 1.04 0.71 1.53 0.843

In multivariate modelling, medications are adjusted for male gender, a history of angina pectoris, hypertension, diabetes (type I or II), a prior AMI, hypercholesterolaemia and lipid-lowering therapy, statins, nitroglycerin, acetosalicylic acid (ASA), β-blockers, Ca-channel blockers, diuretics, ACE-inhibitors or AT2-antagonists, and flecainide, amiodarone or sotalol.

### Doses of psychotropic drugs, concomitant use of alcohol, and circadian rhythms

Among all users of psychotropic drugs, high dose of antipsychotic drugs had been used more commonly among the victims of SCD than the AMI survivors (20 vs. 0%, P= 0.03). The doses of antidepressant drugs did not differ between the groups. Blood alcohol concentration was measured in cases with a suspicion of alcohol use in SCD victims (42%). Among the victims of SCD, alcohol was observed in blood (>0.1‰) more commonly among those using psychotropic drugs (69%) compared with those not using these drugs (57%) (P= 0.002). The exact time of SCD could be defined in 996 of cases. In these cases, the circadian rhythm of SCD was different among those using psychotropic drugs with a higher incidence during the night-time among the drug users (P= 0.040) (Figure 2).

Figure 2

Circadian distribution of sudden cardiac deaths among the users and non-users of psychotropic drugs. Significantly higher incidence of sudden cardiac death was observed during the night hours among the users of psychotropic drugs (P= 0.040).

Figure 2

Circadian distribution of sudden cardiac deaths among the users and non-users of psychotropic drugs. Significantly higher incidence of sudden cardiac death was observed during the night hours among the users of psychotropic drugs (P= 0.040).

## Discussion

The use of psychotropic drugs was more common among the victims of SCD compared with survivors of AMI. Victims of SCD were more commonly users of both antipsychotics and antidepressants. The difference was most prominent in the use of antipsychotics, especially the phenothiazines. In the subgroups of antidepressants, the use of TCAs was more common in the SCD group, whereas there were only borderline differences in the use of SSRIs or newer types of antidepressants. The combined use of both antipsychotic and antidepressant drugs was associated with a very high risk of SCD during a coronary event. The use of cardiovascular drugs, such as aspirin, beta-blocking medication, and angiotensin-converting enzyme inhibitors, was less common among the victims of SCD. However, the difference in the use of psychotropic medication, which was the main focus of the present study, remained significant after adjusting for the use of other medications and other confounding variables.

Previous studies have shown that mental disorders increase the risk of cardiovascular mortality,3–7 but it has not been clearly established if psychiatric disorders, such as depression or schizophrenia, predispose to the occurrence of cardiovascular events or whether they modify the outcome during such events. The present results support the latter proposal, since it was found that the subjects using psychotropic drugs had a higher risk of dying during an acute coronary event, with fatal arrhythmia being the most probable cause of SCD during the ischaemic event. This concept is also supported by studies showing that depression increases specifically the occurrence of SCD but not non-fatal cardiac events.9,11

Previously, two large cohort studies have documented an increased risk of SCD among users of both typical and atypical antipsychotic drugs.13,14 In addition, a dose-dependent risk of SCD has been earlier found for the TCAs.22 In one study,11 the risk of SCD was most prominent in women who used antidepressants, whereas the rate of depression did not confer an elevated risk in the fully adjusted models. In the present study, the victims of SCD used more commonly both TCAs and antipsychotics but the excess use of SSRIs and newer antidepressants was not significant, pointing to a direct drug influence underpinning the mechanism of SCD. The risk of SCD was most strongly associated with the use of phenothiazines. This group includes drugs such as thioridazine, which is the most frequently reported cardiotoxic antipsychotic drug.12 The risk of SCD tended also to be higher in those who used newer types of antipsychotic drugs, although the difference did not remain significant after adjustments for confounding variables, partly supporting the previous data showing that the newer atypical antipsychotic drugs also possess a proarrhythmic potential.14

The causal relationship between the use of psychotropic drugs and SCD during an ischaemic event was further supported by an observation of higher doses of antipsychotic drugs among the victims of SCD as well as a special circadian rhythm of SCD among those using psychotropic drugs with a higher incidence during the night hours. Higher evening doses of psychotropic drugs are commonly used because of their sedative effects. Many patients with psychiatric problems also experience disturbances in their sleep-awake cycle and insomnia, which are reasons to administrate higher doses of psychotropic drugs in the evening. Concomitant alcohol use with psychotropic drugs was also relatively common among the victims of SCD.

A very high risk of SCD was observed in those individuals who were using both antipsychotic and antidepressant medication. The risk was particularly high with phenothiazines combined with antidepressant medication, suggesting that the combined use of these drugs may potentiate their proarrhythmic effects at the time of an acute ischaemic event. The use of benzodiazepines, a class of drugs which do not have any recognized proarrhythmic potential,12 was similar between the groups, suggesting that psychiatric disorders, at least anxiety, does not increase the vulnerability to fatal events, whereas the drugs used for mental disorders have a more marked effect.

The risk of SCD caused by antiarrhythmic drugs has usually been linked to their proarrhythmic effects. These effects have been especially linked to TCAs and antipsychotics,12 but the cascade leading to the fatal arrhythmia induced by these drugs is still not totally clear. Some antipsychotic drugs as well as TCAs have been shown to cause prolongation of the QT-interval in the electrocardiogram, which can lead to malignant polymorphic ventricular arrhythmia, torsades de pointes, and ultimately to sudden death. At the cellular level TCAs, such as imipramine and amitrioptyline, and antipsychotics, such as thioridazine, are associated with inhibition of potassium channels encoded by HERG, which correlates with prolonged QT intervals and a risk of torsades de pointes.23 Differences in risk between classes of psychotropic drugs may result from additional cellular effects of particular drugs, such as from effects on sodium and calcium channels especially at the time of acute myocardial ischaemia and concomitant sympathetic activation. Currently, there is not much data on the electrophysiological effects of psychotropic drugs from ischaemic cellular models, which should obviously be a focus of future research.

Limitation of the study is that we did not have specific diagnoses of mental disorders, and therefore it is possible that depression or schizophrenia may well be important denominators and pathway variables of the observed association between psychotropic drugs and SCD. The case–control design of the study is another potential limitation, because the baseline variables differed significantly between the groups. Furthermore, due to the study design, causality cannot be directly attributed to psychotropic drugs. The time period of collecting the study populations differed slightly, since the timeframe for the control group ended ∼5 years prior to the collection of cases. Nonetheless, the sample size consisted of a consecutive series of AMI survivors from two studies and consecutive victims of SCD from the same geographical area as the AMI survivors, providing information on the characteristics of those subjects dying and those surviving an acute coronary event. The strength of the study is the careful diagnosis of the mode of SCD. The definition of SCD without the autopsy data in previous epidemiological studies may mean that several mechanisms have been involved in the SCD. For example, suicide is a common reason of death in psychotic and depressive patients,24 and it may be difficult to differentiate suicide from SCD in epidemiological studies that do not have access to autopsy evidence with toxicological examinations, which are very comprehensive and reliable in Finland.25

Psychoses and other severe mental disorders are common, and their public health and human importance is enormous. The results of this study provide some insight into the extent and potential mechanisms behind the association between cardiac mortality and various psychiatric disorders and have also some practical implications. Almost 1 out of 10 victims of SCD (9.7%) was using antipsychotic drugs in the present population, whereas the prevalence was only 2.4% in survivors of AMI. The life-time prevalence of psychoses has been reported to be ∼3% in Finland.26 High prevalence of the use of antipsychotics in this study supports the view that the target population for using antipsychotics is wider than just psychoses, perhaps behavioural symptoms, anxiety, depression, etc. Therefore, liberal off-label use of psychotropic drugs, also TCAs, e.g. in the treatment of pain and sleep disorders, should be restricted whenever possible. Patients using both antipsychotic and antidepressants seem to be at a very high risk of dying suddenly during a coronary event, suggesting that if possible this combination should be avoided, especially in those patients who carry other cardiovascular risk factors. In addition, attempts should be focused on preventing coronary events in the subjects suffering from psychiatric disorders and who require treatment with antidepressant and/or antipsychotic medications.

## Funding

This study was supported by Sigrid Juselius Foundation (E.H. and H.V.H.), Helsinki, Finland, and the Foundation Leducq (M.J.J.), Paris, France.

Conflict of interest: none declared.

## Acknowledgements

All authors have contributed to the design of the study, interpretation of results, revising the manuscript, and approve the final version of the manuscript.

## References

1
Huikuri
HV
Castellanos
A
Myerburg
RJ
Sudden death due to cardiac arrhythmias
N Engl J Med
,
2001
, vol.
345
(pg.
1473
-
1482
)
2
Kaikkonen
KS
Kortelainen
ML
Huikuri
HV
Comparison of risk profiles between survivors and victims of sudden cardiac death from an acute coronary event
Ann Med
,
2009
, vol.
41
(pg.
120
-
127
)
3
Carney
RM
Rich
MW
Freedland
KE
Saini
J
teVelde
A
Simeone
C
Clark
K
Major depressive disorder predicts cardiac events in patients with coronary artery disease
Psychosom Med
,
1988
, vol.
50
(pg.
627
-
633
)
4
Newcomer
JW
Hennekens
CH
Severe mental illness and risk of cardiovascular disease
JAMA
,
2007
, vol.
298
(pg.
1794
-
1796
)
5
Van der Kooy
K
van Hout
H
Marwijk
H
Marten
H
Stehouwer
C
Beekman
A
Depression and the risk for cardiovascular diseases: systematic review and meta analysis
Int J Geriatr Psychiatry
,
2007
, vol.
22
(pg.
613
-
626
)
6
Hennekens
CH
Hennekens
AR
Hollar
D
Casey
DE
Schizophrenia and increased risks of cardiovascular disease
Am Heart J
,
2005
, vol.
150
(pg.
1115
-
1121
)
7
Koponen
H
Alaräisänen
A
Saari
K
Pelkonen
O
Huikuri
H
Raatikainen
MJ
Savolainen
M
Isohanni
M
Schizophrenia and sudden cardiac death-a review
Nord J Psychiatry
,
2008
, vol.
62
(pg.
342
-
345
)
8
Irvine
J
Basinski
A
Baker
B
Jandciu
S
Paquette
M
Cairns
J
Connolly
S
Roberts
R
Gent
M
Dorian
P
Depression and risk of sudden cardiac death after acute myocardial infarction: testing for the confounding effects of fatigue
Psychosom Med
,
1999
, vol.
61
(pg.
729
-
737
)
9
Luukinen
H
Laippala
P
Huikuri
HV
Depressive symptoms and the risk of sudden cardiac death among the elderly
Eur Heart J
,
2003
, vol.
24
(pg.
2021
-
2026
)
10
Empana
JP
Jouven
X
Lemaitre
RN
Lemaitre
RN
Sotoodehnia
N
Rea
T
Raghunathan
TE
Simon
G
Siscovick
DS
Clinical depression and risk of out-of-hospital cardiac arrest
Arch Intern Med
,
2006
, vol.
166
(pg.
195
-
200
)
11
Whang
W
Kubzansky
LD
Kawachi
I
Rexrode
KM
Kroenke
CH
Glynn
RJ
GAran
H
Albert
CM
Depression and risk of sudden cardiac death and coronary heart disease in women: results from the Nurses’ Health Study
J Am Coll Cardiol
,
2009
, vol.
53
(pg.
950
-
958
)
12
Kovacs
D
Arora
R
Cardiovascular effects of psychotropic drugs
Am J Ther
,
2008
, vol.
15
(pg.
474
-
483
)
13
Ray
WA
Meredith
S
Thapa
PB
KG
Hall
K
Murray
KT
Antipsychotics and the risk of sudden cardiac death
Arch Gen Psychiatry
,
2001
, vol.
58
(pg.
1168
-
1171
)
14
Ray
WA
Chung
CP
Murray
KT
Hall
K
Stein
CM
Atypical antipsychotic drugs and the risk of sudden cardiac death
N Engl J Med
,
2009
, vol.
360
(pg.
225
-
235
)
15
Kaikkonen
KS
Kortelainen
ML
Linna
E
Huikuri
HV
Family history and the risk of sudden cardiac death as a manifestation of an acute coronary event
Circulation
,
2006
, vol.
114
(pg.
1462
-
1467
)
16
Kaikkonen
K
Risk factors for sudden cardiac death from an acute ischemic event in general population
Acta Univ Oul
,
2009
pg.
33

D 1007
17
Tapanainen
JM
Still
AM
Airaksinen
KE
Huikuri
HV
Prognostic significance of risk stratifiers of mortality including T wave alternans after acute myocardial infarction. Results of a prospective follow-up study
. J Cardiovasc Electrophysiol
,
2001
, vol.
12
(pg.
645
-
652
)
18
Huikuri
HV
Raatikainen
MJP
Moerch-Joergensen
R
Hartikainen
J
Virtanen
V
Boland
J
Anttonen
O
Hoest
N
Boersma
LVA
Platou
ES
Messier
MD
BlochThomsen
P-E
for the Cardiac Arrhythmias and Risk Stratification after Acute Myocardial Infarction (CARISMA) study group
Prediction of fatal or near fatal cardiac arrhythmia events in patients with depressed left ventricular function after an acute myocardial infarction. Results of the Cardiac Arrhythmias and Risk Stratification after Acute Myocardial Infarction (CARISMA) Study
Eur Heart J
,
2009
, vol.
30
(pg.
689
-
698
)
19
Rey
MJ
Schulz
P
Costa
C
Dick
P
Tissot
R
Guidelines of neuroleptics.I: Clorpromazine equivalents of orally administred neuroleptis
Int Clin Psychiatry
,
1989
, vol.
4
(pg.
95
-
104
)
20
Woods
SW
Chlorpromazine equivalemnt doses for the newer atypical antipsychotics
J Clin Psychiatry
,
2003
, vol.
64
(pg.
663
-
667
)
21
WHO
Collaborating Centre for Drug Statistics Methodology
2002

22
Ray
WA
Meredith
S
Thapa
PB
Hall
K
Murray
KT
Cyclic antidepressants and the risk of sudden cardiac death
Clin Pharmacol Ther
,
2004
, vol.
75
(pg.
234
-
241
)
23
Witchel
HJJ
Hancox
JC
Nutt
DJ
Psychotropic drugs, cardiac arrhythmia, and sudden death
J Clin Psychopharm
,
2003
, vol.
23
(pg.
58
-
77
)
24
ED
Haas
GL
Mann
JJ
Sweeney
JA
Suicidal behavior in patients with schizophrenia and other psychotic disorders
Am J Psychiatry
,
1999
, vol.
156
(pg.
1590
-
1595
)
25
Lahti
RA
Penttilä
A
The validity of death certificates: routine validation of death certification and its effects on mortality statistics
Forensic Sci Int
,
2001
, vol.
115
(pg.
15
-
23
)
26
Perälä
J
Suvisaari
J
Saarni
SI
Kuoppasalmi
K
Isometsä
E
Pirkola
S
Partonen
T
Tuulio-Henriksson
A
Hintikka
J
Kieseppä
T
Härkänen
T
Koskinen
S
Lönnqvist
J
Lifetime prevalence of psychotic and bipolar I disorders in a general population
Arch Gen Psychiatry
,
2007
, vol.
64
(pg.
19
-
28
)

## Supplementary data

Reply to Psychotropic medications and the risk of sudden cardiac death during an acute coronary event
9 October 2011
Alan Watson

I believe that the conundrum of psychotropic medications and the risk of sudden cardiac death may be easily explained by analysis of the pharmacology of the drugs implicated. The one thing the culprits all share is alpha adrenergic receptor blocking activity1.

The greater the degree of alpha adrenergic receptor blockade the greater the risk of sudden cardiac death. Hence combinations of alpha blockers add to risk as does higher dosages. Drugs such as the benzodiazepines have no alpha receptor blocking action hence the studies finding that there was no difference in the use of benzodiazepines between the victims of sudden cardiac death and the survivors of acute myocardial infarction.

The explanation for the sudden cardiac deaths in alpha adrenergic blocked patients could be multifactorial. There is evidence the the typical and the atypical antipsychotics increase the QT interval predisposing to malignant ventricular arrhythmias2. In my opinion this is an alpha adrenergic receptor blocking phenomenon. In a flight or fight situation the adrenergic surge increases the number of heart beats per minute with more rapid conduction in the cardiac conduction system facilitating this response. It appears logical that blocking of alpha adrenergic receptors would have the opposite effect on the cardiac conduction system!

The reverse adrenaline effect could be another logical explanation implicating the common alpha adrenegic receptor blocking activity of the culprits3. Hypotension in alpha receptor blocked patients e.g. from acute myocardial infarction, anaphlaxis, vasovagal would be exacerbated by adrenaline, endogenous (fight or flight) or exogenous physician/paramedic) predisposing to a malignant arrhythmia or to death from hypotension per se.

Sudden cardiac deaths are very rare and the psychotropics and antidepressants are managing serious life threatening mental illneses. I endorse the authors perspective however regarding off label prescribing of antipsychotics and and tricyclic antidepressants in the treatment of pain and sleep disoders and I recommend equal restraint regarding use of alpha adrenergic receptor blocking drugs for prostatism and hypertension4.

Alan Watson

1. Watson A. Alpha adrenergic blockers and adrenaline- a mysterious collapse. Australain Family Physician Vol. 27 No 8, August 1998 714-715.

2. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Eng J Med 2009; 360:225-235

3. Goodman & Gilman's the Pharmacological Basis of Therapeutics.

4. Watson A. Don't get stung with the adrenergic blockers (beta or alpha). Australian Family Physician Vol. 24, No. 10, October 1995 1879.

### Conflict of Interest:

None declared

Submitted on 09/10/2011 8:00 PM GMT
Psychotropic drugs and sudden death
9 October 2011
Heikki V. Huikuri (with Juhani Junttila)

Dr. Alan Watson suggested in his letter that the association between the use of psychotropic drugs and sudden cardiac death could be explained by the alpha adrenergic blocking effects of these drugs.

This is an interesting explanation, but we are not at all convinced on this theory. He proposes that QT interval prolongation would be an alpha adrenergic receptor blocking phenomenon. However, there is evidence that alpha adrenergic agonists prolong repolarization and consequently alpha adrenergic blocking agents attenuate, not accentuate, this prolongation (1). Prolongation of repolarization by the antipsychotic and tricyclic antidepressant drugs is commonly explained by the their IKr blocking effects, which is not significantly modulated by alpha adrenergic drugs. Experimental data also show that at the time of ischemia, the response of alpha adrenergic stimulation becomes arrhythmogenic rather than antiarrhythmic (2). This does not support the concept that alpha- adrenergic receptor blockade would be harmful in this context. Furthermore, we are not aware of any clinical studies showing that "pure" alpha-adrenergic blocking drugs would increase the risk of sudden cardiac death. Finally, we must disagree with the concept that sudden cardiac deaths are "very rare". The epidemiological and register data show that sudden cardiac death, which is due to an acute ischemic event in 80% of the cases, is the most common single cause of mortality in western societies (3), accounting almost as many deaths than all cancers together and more than traffic accidents and suicides together. We certainly agree that patients with serious mental illnesses must use psychotropic drugs, but more attention should be paid on prevention of acute coronary events in these patients and the widespread off-label use of psychotropic drugs in attempts to reduce the global risk of unexpected sudden deaths.

References:

1. Giotti A, Ledda F, Mannaioni PF. Effects of noradrenaline and isoprenaline, in combination with alpha- and beta-receptor blocking substances, on the action potential duration of cardiac Purkinje fibers. J Physiol 1973;299:99-113

2. Coo PB, Shayman JA, Kramer. Increased alpha adrenergic receptors in ischemic cat myocardium: A potential mediator of electrophysiologic derangements. J Clin Invest 1981; 67:1232-1236

3. Huikuri HV, Castellanos A, Myerburg R. Sudden death due to cardiac arrhythmias. N Engl J Med 2001; 345:1473-1482

Heikki Huikuri, MD, Professor of Medicine Juhani Junttila, MD.

### Conflict of Interest:

None declared

Submitted on 09/10/2011 8:00 PM GMT
Re:Psychotropic drugs and sudden death
28 December 2011
Fred A Jr Baughman (with Mr. Stan White)
Home > Veteran News > Hundreds of Soldiers & Vets Dying From Antipsychotic - Seroquel Hundreds of Soldiers & Vets Dying From Antipsychotic - Seroquel EL CAJON, Calif., Nov. 7, 2011 /PRNewswire/ -- As a neurologist who has discovered and described medical diseases, I (FAB) read the May 24, 2008, Charleston (WV) Gazette article "Vets taking Post Traumatic Stress Disorder drugs die in sleep," and opened and financed my own investigation into these unexplained deaths. Andrew White, Eric Layne, Nicholas Endicott and Derek Johnson, all in their twenties, were four West Virginia veterans who died in their sleep in early 2008. There were no signs of suicide or of a multi-drug "overdose" leading to coma, as claimed by the Inspector General of the VA. All had been diagnosed "PTSD"--a psychological diagnosis, not a disease (physical abnormality) of the brain. All were on the same prescribed drug cocktail, Seroquel (antipsychotic), Paxil (antidepressant) and Klonopin (benzodiazepine) and all appeared "normal" when they went to sleep. On February 7, 2008, Surgeon General Eric B. Schoomaker, had announced there had been "a series, a sequence of deaths" in the military suggesting this was "often a consequence of the use of multiple prescription and nonprescription medicines and alcohol." However, the deaths of the 'Charleston Four' were probable sudden cardiac deaths (SCD), a sudden, pulseless condition leading to brain death in 4-5 minutes, a survival rate or 3-4%, and not allowing time for transfer to a hospital. Conversely, drug-overdose coma is protracted, allowing time for discovery, diagnosis, transport, treatment, and frequently-survival. Antipsychotics and antidepressants alone or in combination, are known to cause SCD. Sicouri and Antzelevitch (2008) concluded: (1) "A number of antipsychotic and antidepressant drugs can increase the risk of ventricular arrhythmias and sudden cardiac death," (2)"Antipsychotics can increase cardiac risk even at low doses whereas antidepressants do it generally at high doses or in the setting of drug combinations." On April 13, 2009, Baughman wrote the Office of the Surgeon General (OTSGWebPublisher@amedd.army.mil): "On February 7, 2008 the Surgeon General said there had been 'a series, a sequence of deaths.' Has the study of these deaths been published?" On April 17, 2009 the Office of the Surgeon General responded, "The assessment is still pending and has not been released yet." More than a year later and still no explanation, nor further acknowledgement that these deaths even took place. In a press release, (PRNewswire, May 19, 2009) Baughman wrote: "I call upon the military for an immediate embargo of all antipsychotics and antidepressants until there has been a complete, wholly public, clarification of the extent and causes of this epidemic of probable sudden cardiac deaths." Googling "dead in bed," "dead in barracks," by April 16, 2009, veteran's wife, Diane Vande Burgt, had Googled 74 probable sudden cardiac deaths. By May 2010: 128, and, by November 2, 2011: 247. Two-hundred-forty-seven! In April 2010 I was in anonymous receipt of an Army National Guard Serious Incident Report for the 5 months 10/03/09 to 3/7/10. In it were 93 "incidents" including 4 "heart attacks," 6 "cardiac arrests" and 3 "found dead"; 13 of 93 (14%) probable SCDs. Pfc. Ryan Alderman, was on a cocktail of psych drugs when found unresponsive, dying in his barracks at Ft. Carson, Colo. Sudden cardiac death was confirmed by an ECG done at the scene. Inexplicably, military officials de-classified his death and reversed the cause, calling it instead, a "suicide." Again I challenge the military to produce the evidence. In June 2011, a DoD Health Advisory Group backed a highly questionable policy of "polypharmacy" asserting: "...multiple psychotropic meds may be appropriate in select individuals." The fact of the matter is that psychotropic drug polypharmacy is never safe, scientific, or medically justifiable. What it is a means of (1) maximizing profit, and (2) making it difficult to impossible to blame adverse effects on any one drug. From 2001 to the present, US Central Command has given deploying troops 180 day supplies of prescription psychotropic drugs--Seroquel included. In a May 2010 report of its Pain Management Task Force, the Army endorsed Seroquel in 25- or 50-milligram doses as a 'sleep aid.' Over the past decade, $717 million was spent for Risperdal and$846 million for Seroquel, for a mind-blowing total of \$1.5 billion when neither Risperdal nor Seroquel have been proven safe or effective for PTSD or sleep disorders. Ironically, yet not surprisingly, pay-to-play in Washington becomes more egregious every day. Heather Bresch, daughter of U.S. Sen. Joe Manchin, (D-WV) was recently named CEO of WV drug-maker Mylan Inc., that recently contracted with the DoD for over 20 million doses of Seroquel. Defense Department Health Advisory Group chair, Charles Fogelman, warned: "DoD currently lacks a unified pharmacy database that reflects medication use across pre-deployment, deployment and post-deployment settings." In essence, through a premeditated lack of record keeping, mandated by law at any other pharmacy or medical office to track potential fatal reactions to mixing prescription drugs, the military is willfully preempting all investigations into the injuries and deaths due to psychiatric drugs. I call on the DoD, VA, House and Senate Armed Services and House and Senate Veterans Affairs Committees to tell concerned Americans and the families of fallen heroes what psychiatric drugs each of the deceased, both combat and non-combat, soldiers and veterans were on? It is time for the military and government to come clean. SOURCE Fred A. Baughman Jr., MD

### Conflict of Interest:

None declared

Submitted on 28/12/2011 7:00 PM GMT
"Response to ""Psychotropic medications and the risk of sudden cardiac death during an acute coronary event"""
17 June 2012
Carol L. Wilson (with Alasdair G. Rooney, Stephen M. Lawrie)

We read this study with great interest and are pleased to see the collaboration between cardiologists and psychiatrists but have concerns that the published results may overestimate the association between risk of death during an acute coronary event and prescribed psychotropic medication.

The paper in which the recruitment of the control group was originally described (J Cardiovasc Electrophysiol 2001;12:645-652) reveals that patients were excluded from the control group if they had dementia, alcoholism, drug abuse or a condition that could impair capacity to give informed consent. All of these are more likely in patients who are prescribed psychotropic medication and therefore have contributed to a sampling bias. Indeed, the Sudden Cardiac Death (SCD) group were significantly more likely to have consumed alcohol prior to their death if they were prescribed psychotropic medication than if they were not. Additionally, the control group was required to undertake an exercise test and 24 hour ECG monitoring, which may have further reduced the inclusion of the mentally ill. It is also possible that patients with more severe disorders would have been less likely to be recruited. It would, therefore, not be surprising to find that those on combinations of psychotropics, those on higher doses and those on treatments that are typically 'second line' would be the least likely of all to be included in the control group. The analysis would, therefore, over-estimate the risk disproportionately for these particular patients. Indeed, the study does not find a statistically significant association between sudden cardiac death during acute infarction and SSRIs or newer 'atypical' antipsychotics following multivariate analysis.

It is also remarkable that cases appear to be significantly less likely to have conventional cardiac risk factors than those who survived. The cases might well have been less engaged with healthcare professionals and less well evaluated for the presence of cardiac risk factors. This theory seems to be supported by the data that those in the SCD group were almost 7 times less likely to have been diagnosed with hypercholesterolaemia than those who survived. For controls the data on previous cardiovascular disease was taken from hospital case notes during an admission for myocardial infarction where such past medical history is likely to be sought and clearly documented. It is otherwise difficult to explain how hypercholesterolaemia, diabetes, hypertension, angina pectoris and a history of previous myocardial infarction were all relatively protective against SCD during a myocardial infarction. Including such data in the multivariate analysis might serve to further over-estimate the association between psychotropic medication and SCD.

We would like to close by acknowledging that this is an important study but maintain that it does require careful interpretation.

### Conflict of Interest:

None declared

Submitted on 17/06/2012 8:00 PM GMT