Schizophrenia Research 168 (2015) 395–401

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Schizophrenia Research

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Risk factors for sudden cardiac death among patients with schizophrenia
Ping-Yi Hou a,b, Galen Chin-Lun Hung a,c, Jia-Rong Jhong a, Shang-Ying Tsai d,e,
Chiao-Chicy Chen d,e,f,g, Chian-Jue Kuo a,d,e,⁎
a
Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan
b
Mei-De Branch, Lee General Hospital, Taichung, Taiwan
c
Department of Public Health, School of Medicine, National Yang Ming University, Taipei, Taiwan
d
Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan
e
Psychiatric Research Center, Taipei Medical University Hospital, Taipei, Taiwan
f
Department of Psychiatry, Mackay Memorial Hospital, Taipei, Taiwan
g
Department of Psychiatry, Mackay Medical College, Taipei, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: Patients with schizophrenia suffer from excessive premature mortality, and sudden cardiac death
Received 18 March 2015 (SCD) is receiving growing attention as a potential cause.
Received in revised form 20 June 2015 Aim: The present study investigated the incidence of SCD and its risk factors in a large schizophrenia cohort.
Accepted 9 July 2015 Methods: We enrolled a consecutive series of 8264 patients diagnosed with schizophrenia (according to DSM-III-
Available online 22 July 2015
R and DSM-IV criteria) who were admitted to a psychiatric center in northern Taiwan from January 1, 1985
through December 31, 2008. By linking with national mortality database, 64 cases of SCD were identified. The
Keywords:
Sudden cardiac death
standardized mortality ratio (SMR) for SCD was estimated. The cases were matched with controls randomly
Risk factor selected using risk-set sampling in a 1:2 ratio. A standardized chart review process was used to collect socio-
Aggression demographic and clinical characteristics and the prescribed drugs for each study subject. Multivariate conditional
Antipsychotics logistic regression analysis was used to identify correlates of SCD at the index admission and the latest admission.
Schizophrenia Results: The SMR for SCD was 4.5. For the clinical profiles at the index admission, physical disease (adjusted risk
ratio [aRR] = 2.91, P b .01) and aggressive behaviors (aRR = 3.99, P b .01) were associated with the risk of SCD.
Regarding the latest admission, electrocardiographic abnormalities (aRR = 5.46, P b .05) and administration of
first-generation antipsychotics (aRR = 5.13, P b .01) elevated the risk for SCD. Consistently, aggressive behaviors
(aRR = 3.26, P b .05) were associated with increased risk as well.
Conclusions: Apart from cardiovascular profiles and antipsychotics, physical aggression is a crucial risk factor that
deserves ongoing work for clarifying the mechanisms mediating SCD in schizophrenia.
© 2015 Elsevier B.V. All rights reserved.

1. Introduction
Schizophrenia is a debilitating disease that affects 1% of the world
population and often leads a deteriorating course and premature
mortality. The life expectancy of patients with schizophrenia is
10–25 years shorter than that of the general population, and it has not
had improvements similar to the general population during the past de-
cade (Crump et al., 2013). The standardized mortality ratios (SMRs)
range from 2 to 4 for patients with schizophrenia depending on the
cause of death. Additionally, the SMRs have escalated for all leading
causes of death for the past 20 years (Saha et al., 2007). One possible ex-
planation for their shorter life expectancy is a tendency toward unnatu-
ral deaths such as suicides, accidents, violence, and substance abuse
⁎ Corresponding author at: Department of General Psychiatry, Taipei City Psychiatric
Center, 309 Sung-Te Road, Taipei 110, Taiwan.
E-mail address: tcpckuo@seed.net.tw (C.-J. Kuo).
(Crump et al., 2013; Saha et al., 2007; Sweeting et al., 2013). Nonethe-
less, two-thirds of the premature deaths among patients with schizo-
phrenia are, in fact, accounted for by natural causes, with 40%–50% of
them being due to cardiovascular diseases (Sweeting et al., 2013).
In the psychiatric care community, concerns are amplified regarding
the possibility of increased risk of sudden cardiac death (SCD) in
patients with schizophrenia. SCD is reported to be three times as likely
among patients with schizophrenia as among individuals from the
general population (Davidson, 2002), and myocardial infarction may ac-
count for over half of the cases (Ifteni et al., 2014). SCD is typically de-
fined as death due to a cardiac cause within a short time (minutes to
hours) after the symptoms initially appear. The symptoms often occur
without warning, which inevitably triggers an inspection of the entire
therapeutic process afterward, searching for preventable causes
(Davidson, 2002; Laursen et al., 2011). Risk factors for SCD in the gener-
al population are not well established, but age, smoking, metabolic pro-
file (e.g., hyperlipidemia, hypertension, glucose intolerance, obesity),

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396 P.-Y. Hou et al. / Schizophrenia Research 168 (2015) 395–401
cardiac conditions (e.g., tachycardia, left ventricular hypertrophy, intra-
ventricular conduction block), and decreased pulmonary vital capacity
are implicated (Straus et al., 2004a).
It is well known that patients with schizophrenia are predisposed to
cardiovascular diseases, and antipsychotics may aggravate such risk
(Newcomer, 2007; Scigliano and Ronchetti, 2013), setting the stage
for lethal arrhythmia or myocardial infarction to occur. The most
established risk factor of SCD in schizophrenia is antipsychotic
exposure. Patients receiving antipsychotics have a greater risk than
non-users to die prematurely of SCD (Girardin et al., 2013; Sweeting
et al., 2013), and the association is dose-dependent (Ray et al., 2001).
First-generation and low-potency antipsychotics appear to carry an
unusually higher liability, whereas second-generation antipsychotics
may ameliorate such risk (Kiviniemi et al., 2013).
Apart from antipsychotic exposure, prior research shows that the
risk factors for SCD in schizophrenia are mostly related to cardiac
arrhythmia (e.g., prolonged QTc interval and Torsade de Pointes)
(Glassman and Bigger, 2001; Suvisaari et al., 2010). Intriguingly, a com-
prehensive exploration of potential risk factors, including demographic
characteristics, cardiovascular diseases, psychopathology, and laborato-
ry markers, is rarely performed. Accordingly, we explored the incidence
and risk factors for SCD in a large, hospital-based schizophrenia cohort.
Potential correlates of multiples dimensions were being assessed,
including demographics, psychopathology, physical illnesses, laborato-
ry markers, and electrocardiography findings.
2. Methods
2.1. Study population
We enrolled patients with schizophrenia who were consecutively
admitted to a psychiatric service center in northern Taiwan from Janu-
ary 1, 1985 to December 31, 2008. The methodology used is described
extensively elsewhere (Kuo et al., 2011). In short, we included patients
who at each discharge received a consistent principal diagnosis of
schizophrenia (ICD-9 code 295.**) which was made after a diagnostic
interview during admission and reconfirmed by a board-certified psy-
chiatrist in charge. Some 8264 patients met the inclusion criteria and
comprised the study cohort. In the present study, information regarding
both the index admission and the latest admission prior to SCD were
included. This study was approved by the Institutional Review Board
of the Committee on Human Subjects of Taipei City Hospital, Taipei,
Taiwan.
2.2. Case ascertainment
Each cohort member was electronically linked, by using the national
identification number as an identifier, with the Department of Health
Death Certification System in Taiwan from January 1, 1985 through
December 31, 2008. Subsequently, we identified 867 deaths along
with the cause of death (Fig. 1). Of those 867 patients who died, 64
died of SCD. SCD was defined as a death reported as occurring out of
hospital or in the emergency room or as “dead on arrival” with an un-
derlying cause of death reported as cardiac disease. The underlying
cause of death included ICD-9 codes 390 to 398, 402, and 404 to 429,
consistent with the criteria adopted in prior studies (Chugh et al.,
2004; Zheng et al., 2001). Of SCD, coronary artery diseases (ICD-9
codes) included acute myocardial infarction (410), other acute and sub-
acute forms of ischemic heart disease (411), old myocardial infarction
(412), angina pectoris (413), and other forms of chronic ischemic
heart disease (414). We then calculated SMRs for all causes of death.
2.3. Nested case–control study
Derived from the study cohort (N = 8264), we conducted a nested
case–control study to explore potential risk factors associated with
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SCD by means of a time-consuming and comprehensive chart review
process. This study was conducted within a cohort in which further
information (perhaps from expensive or time-consuming tests) was ob-
tained on most or all the case subjects, but for economy, was obtained
from only a fraction of the remaining cohort subjects as the controls
(Greenland, 2008). Typically, case–control studies involve a cumulative
design in which controls are selected from non-cases at the end of a
follow-up period (Greenland, 2008). However, the strategy of risk-set
sampling for obtaining controls has an advantage, in which has poten-
tially much less sensitivity to bias from exposure-related loss-to-
follow-up, as noted by epidemiologists (Greenland and Thomas, 1982;
Miettinen, 1976). We used this methodology to select controls in previ-
ous studies (Kuo et al., 2011, 2012; Pan et al., 2014). Based on risk-set
sampling, this study selected two or fewer controls randomly for each
case participant, matched for age (±5 years), gender, and the year of
index admission. The index admission was defined as the earliest hospi-
talization during the study period. Additionally, controls were selected
from cohort patients who were alive at the time of death of the corre-
sponding case. Thus, cases that were identified later during the study
period were eligible to serve as controls for earlier cases. Consequently,
53 cases were successfully paired with 103 controls; controls were un-
available or had incomplete information for 11 cases. In 50 case–control
pairs, two controls were selected for each case. One control was chosen
for each case in three pairs.
2.4. Data collection
A semi-structured form was used for any inpatient who was admit-
ted to the Taipei City Psychiatric Center since 1980 (Kuo et al., 2011).
The form collected clinical information and contained over 95 items in-
cluding sociodemographic information and a detailed psychiatric evalu-
ation, including the diagnosis, mental state examination, family history,
and physical diseases. We used this form to collate clinical information
in prior studies (Kuo et al., 2011). For each inpatient, a resident
psychiatrist and a board-certified psychiatrist conducted semi-
structured interviews for obtaining relevant clinical information during
hospitalization. In addition, a fasting venous blood sample was routinely
drawn for biochemical and serological analyses on the first morning
after hospitalization. After hospitalization, a 12-lead electrocardiogra-
phy (ECG) examination was immediately performed on each subject.
By means of a combined chart review process by two trained clinical
psychologists and double checking by a senior psychiatrist (CJK),
detailed information on each subject was obtained. We developed a struc-
tured concept form comprising 115 items for helping the review process.
Typically, for each patient, 40 min were required to obtain the informa-
tion regarding demographic status, social support, employment history,
psychiatric comorbidity, the prescription of psychotropics (antipsychotics
and antidepressants), symptom profile, other clinical features
(e.g., suicide attempt, aggressive behaviors, physical diseases), and labo-
ratory data related to the index and latest (most recent) hospital admis-
sions, respectively. We measured the defined daily dose (DDD) of
antipsychotics use based on the dosage information obtained from the
Anatomical Therapeutic Chemical Classification system (ATC/DDD Index
2009. http://www.whocc.no/atc_ddd_index/ [accessed May 1, 2009])
(WHO Collaborating Centre for Drug Statistic Methodology, 2009). For ex-
ample, 8 mg of haloperidol used daily was equal to one DDD.
The chart reviewers were blinded to the mortality status. All
reviewers participated in a reliability study (Kuo et al., 2011), rating
information for four cases and eight controls independently, with
kappa values greater than 0.7 for all key variables, including symptom
profiles, comorbidity, and suicide attempt.
2.5. Statistical analyses
First, we estimated the SMRs. The survival time for each subject was
calculated from the index discharge to the end of the study. SMRs for
 P.-Y. Hou et al. / Schizophrenia Research 168 (2015) 395–401 397

All patients who were admitted to

Taipei City Psychiatric Center
(Taiwan) from 1985 to 2008 (N =
24,386)

Patients with a consistent diagnosis

of schizophrenia (ICD-9 code of
295.**) between 1985 and 2008 (N
= 8,264) as the study cohort

Linking with mortality database

(1985/1/1 to 2008/12/31)

Patients with all-cause mortality (N

= 867)
Standardized mortality ratio (SMRs)
for each cause of death were
estimated
Patients with sudden cardiac death
(ICD 9 codes 390 to 398, 402, or
404 to 429) during the study period
was defined as the cases (N = 64)

Two controls were selected from the

study cohort for each case, matched
with gender, age (±5 y/o), and year
of first admission

Finally, 53 valid case-control pairs

(53:103) were studied due to 11
cases without available controls
or information

Fig. 1. Study flow diagram.

all-cause and SCD were calculated by dividing the observed number of
deaths by the expected number of deaths, which was estimated based
on mortality rate of the general population in Taiwan. We used Poisson
regression to analyze gender differences for SMRs by means of Egret for
Windows (version 2.0.31). The P values of the relative SMRs, i.e., the
SMRs for women relative to that of men, were calculated.
Secondly, we initially used univariate logistic regression to examine
the distribution of unmatched factors between case subjects and living
controls. Then, those variables with potential association (P b .05) were
entered into multivariate models for the adjustment. We conducted
multivariate models based on a backward variable selection strategy
using the Proc Phreg function of SAS software, version 9.2 (SAS Institutes,
Inc., Cary, NC, USA). Depending on the variables at two time points
(i.e., index admission, latest admission), two exploratory models were
employed, respectively. A P value of .05 was considered significant.
3. Results
3.1. Incidence and SMR of SCD
Relative to the general population, the schizophrenia cohort had
excessive all-cause mortality (SMR = 4.5), with the magnitude of
natural death (SMR = 3.5) less than unnatural death (SMR = 7.2).
There were 64 verified cases of SCD, yielding an incidence of 81.4 per
100,000 person-years (64 cases/78,625.9 total contributed person-
years) and an SMR of 4.5. There were no differences in the SMRs for
SCD between men and women (P = .258). Data regarding SMR for
each cause of death is available in online Supplemental e-Table 1.
3.2. Demographic characteristics
Of the 53 available case–control pairs in the nested case–control
study, case subjects and living controls had similar distributions of mar-
ital status, living with family, educational level, employment, and socio-
economic status according to Hollingshead's classification (Hollingshead
and Rhdlich, 1958) (Table 1) at the index admission. No one died during
the index admission. There was no significant difference between the
cases and controls regarding the age at the index admission, the onset
age of schizophrenia, and the disease duration from the onset to the
index admission.
In SCD cases, mean age at the index admission was 46.0 (SD = 15.8)
years; mean duration between index admission and SCD was 5.4
(SD = 4.9) years; mean duration between latest admission and SCD
was 4.7 (SD = 4.3) years. Notably, in 43 of 53 cases, the index admission
was same as the latest admission; in 55 of 103 controls, the index
admission was same as the latest admission. The specific causes of
SCD included coronary artery diseases (n = 18), arrhythmia (n = 12),
congestive heart failure (n = 11), hypertensive heart disease (n = 1),

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Table 1
Demographic information of cases with sudden cardiac death and living controls (1:2 ratio) among patients with schizophrenia at the index admission.

Characteristic Cases Controls Unadjusted 95% CI P

(n = 53) (n = 103) risk ratioa

Index admission n (%) n (%)

Gender
Male 29 (54.7) 57 (55.3) … … …
Female 24 (45.3) 46 (44.7) … … …
Married 13 (24.5) 33 (32.7) 0.59 0.26–1.35 0.211
Living with family 42 (79.3) 78 (75.7) 1.30 0.51–3.35 0.582
Education, N12 years 9 (17.7) 23 (22.8) 0.67 0.27–1.70 0.400
Employed 4 (7.6) 16 (15.7) 0.45 0.14–1.44 0.180
Hollingshead socio-economic status, class IV or V 51 (100.0) 96 (95.1) – – –

Mean (SD) Mean (SD)

Age, y/o 46.0 (15.8) 44.1 (15.5) 1.10 0.98–1.24 0.113

The onset of schizophrenia, y/o 30.1 (13.5) 32.6 (13.3) 0.97 0.94–1.01 0.153
The duration from the onset to the index admission, years 15.1 (12.2) 11.5 (11.6) 1.04 1.00–1.08 0.057

Symbol: … = matched by design.

a
Estimated using univariate conditional logistic regression.

and ill-defined descriptions and complications of heart disease
(n = 11). Further detailed causes of coronary artery diseases (n = 18)
included acute myocardial infarction (n = 16), old myocardial infarc-
tion (n = 1), and other forms of chronic ischemic heart disease (n = 1).
3.3. Clinical predictors of SCD
Univariate analysis showed that at the index admission (Table 2),
cases had greater proportions of aggressive behaviors (unadjusted risk
ratio [RR] = 3.51, P = .007) and physical diseases (unadjusted
RR = 2.85, P = .004) than controls. The prevalences of cardiovascular
diseases and diabetes were similar. There were no detectable differ-
ences regarding the metabolic profiles including body mass index,
fasting glucose, cholesterol, and triglyceride. The single observable
laboratory difference was that cases had slightly higher sodium levels
(unadjusted RR = 1.15, P = .047).
As for the latest admission, cases had a significantly greater propor-
tion of first-generation antipsychotic monotherapy than controls

Table 2
Clinical characteristics of cases with sudden cardiac death and living controls among patients with schizophrenia at the index admission and the latest admission respectively.

Characteristic Index admission Latest admission

Cases Controls Unadjusted P Cases Controls Unadjusted P

(n = 53) (n = 103) risk ratio (n = 53) (n = 103) risk ratio

n (%) n (%) n (%) n (%)

Comorbidity
Substance use disorders 4 (7.6) 1 (1.0) 8.00 0.063 2 (3.8) 2 (1.9) 2.00 0.488
Psychosis-related symptoms
Auditory hallucination 44 (83.0) 77 (74.8) 1.63 0.261 41 (77.4) 64 (62.1) 1.95 0.076
Visual hallucination 13 (24.5) 21 (20.4) 1.32 0.518 14 (26.4) 14 (13.6) 2.24 0.058
Persecutory delusion 38 (71.7) 74 (71.8) 0.98 0.952 39 (73.6) 65 (63.1) 1.62 0.207
Behaviors
Suicide behavior 0 (–) 1 (1.0) 0.00 0.995 1 (1.9) 1 (1.0) 2.00 0.624
Behaving aggressively to people 17 (32.1) 13 (12.6) 3.51⁎⁎ 0.007 18 (34.0) 12 (11.7) 4.38⁎⁎ 0.002
Abnormal ECG 9 (18.4) 9 (10.0) 2.28 0.182 8 (17.4) 4 (4.4) 4.39⁎ 0.033
Physical diseases 33 (62.3) 38 (36.9) 2.85⁎⁎ 0.004 31 (58.5) 44 (42.7) 1.88 0.076
Cardiovascular diseases 7 (13.2) 12 (11.7) 1.12 0.845 7 (13.2) 14 (13.6) 0.90 0.850
Diabetes 3 (5.7) 5 (4.9) 1.36 0.692 3 (5.7) 7 (6.8) 1.11 0.895
Any antidepressant 2 (3.8) 6 (5.8) 0.67 0.620 4 (7.6) 8 (7.8) 0.93 0.916
Antipsychotic used 51 (96.2) 96 (93.2) 1.86 0.459 51 (96.2) 95 (92.2) 2.30 0.328
Both FGA and SGA 0 (–) 1 (1.0) 0.00 0.995 0 (–) 2 (1.9) 0.00 0.992
Only FGA used 43 (81.1) 76 (73.8) 1.93 0.203 41 (77.4) 59 (57.3) 3.78⁎ 0.006
Only SGA used 8 (15.1) 19 (18.5) 0.66 0.471 10 (18.9) 34 (33.0) 0.35⁎ 0.031

Mean (SD) Mean (SD) Mean (SD) Mean (SD)

Antipsychotic dose (unit as the defined daily dose, DDD)

Haloperidol 0.52 (0.7) 0.38 (0.7) 1.28 0.2695 0.51 (0.8) 0.23 (0.5) 1.86⁎ 0.019
Risperidone 0.05 (0.2) 0.07 (0.2) 0.58 0.5333 0.06 (0.2) 0.14 (0.3) 0.31 0.126
Body mass index (BMI) 24.3 (5.2) 22.8 (3.9) 1.09 0.059 24.5 (5.4) 23.2 (3.9) 1.08 0.081
Laboratory marker
Fasting glucose (mg/dL) 100.6 (24.2) 102.3 (40.2) 1.00 0.790 103.2 (30.3) 102.0 (43.1) 1.00 0.909
Serum cholesterol (mg/dL) 194.7 (42.0) 188.9 (38.3) 1.00 0.443 193.5 (41.9) 188.4 (40.0) 1.00 0.427
Serum triglyceride (mg/dL) 132.9 (68.1) 114.4 (55.8) 1.01 0.135 126.3 (69.1) 124.1 (71.7) 1.00 0.465
Albumin (g/dL) 4.2 (0.4) 4.2 (0.4) 0.95 0.906 4.2 (0.4) 4.2 (0.5) 0.90 0.793
Sodium (Na) (mmol/L) 142.9 (3.6) 141.8 (3.0) 1.15⁎ 0.047 143.0 (3.7) 143.0 (31.2) 1.00 0.988
Potassium (K) (mmol/L) 4.0 (0.4) 4.0 (0.4) 1.44 0.413 4.0 (0.4) 5.1 (10.5) 0.94 0.822
Leucocytes (×103/μL) 7515.8 (3144.7) 6657.8 (2658.7) 1.00 0.056 7319.5 (3275.4) 6744.6 (2803.4) 1.00 0.174
Hemoglobin (mg/dL) 13.7 (1.7) 13.6 (2.0) 1.12 0.356 13.6 (1.6) 16.3 (27.5) 0.99 0.675

FGA: first-generation antipsychotics; SGA: second-generation antipsychotics; ECG: electrocardiogram.

⁎ P b 0.05.
⁎⁎ P b 0.01.

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 P.-Y. Hou et al. / Schizophrenia Research 168 (2015) 395–401
(unadjusted RR = 3.78, P = .006); taking haloperidol as an example,
this association was dose-dependent (unadjusted RR = 1.86,
P = .019). On the contrary, second-generation antipsychotic
(SGA) monotherapy was associated with a 65% reduced risk of SCD
(unadjusted RR = 0.35, P = .031). Similar to the index admission,
aggressive behaviors were much more prevalent in cases than in
controls (unadjusted RR = 4.38, P = 0.002). The only laboratory differ-
ence was that the proportion of ECG abnormalities in cases was higher
than the controls (unadjusted RR = 4.39, P = .033).
3.4. Multivariate logistic regression modeling
Two sets of multivariate regression analysis were performed, one for
variables of the index admission and the other for those of the latest ad-
mission. At the index admission (Model 1), two variables associated
with SCD became apparent. They were aggressive behaviors (adjusted
RR = 3.99, P = .006) and physical diseases (adjusted RR = 2.91,
P = .005). As for the variables at the latest admission (Model 2), three
variables developed. Consistently, aggressive behaviors remained as a
significant predictor of SCD (adjusted RR = 3.26, P = .04). Use of any
first-generation antipsychotic was associated with SCD (adjusted
RR = 5.13, P = .006). Moreover, ECG abnormalities significantly elevat-
ed the risk of SCD (adjusted RR = 5.46, P = .033).
4. Discussion
4.1. Main findings
We investigated the first large cohort of patients with schizophrenia
in the Asian population to determine the incidence of SCD and its risk
factors. Our results are consistent with prior research demonstrating a
higher incidence of SCD in patients with schizophrenia (Chute et al.,
1999; Cohen et al., 2001; Davidson, 2002; Ifteni et al., 2014). The excep-
tionally high SMR of 4.5 demands preventive efforts. By using the nested
case–control study design, which was clear for a temporal sequence, we
explored the factors associated with SCD. We confirmed the conven-
tional risk factors including physical diseases, ECG abnormalities, and
administration of first-generation antipsychotics; intriguingly, we
showed that a history of aggressive behaviors is strongly associated
with SCD in patients with schizophrenia.
4.2. ECG abnormality as a risk factor for SCD
ECG is a primary method for identifying cardiovascular disease, and
the instrument (electrocardiograph) is non-invasive and could be easily
applied in routine examinations. However, the literature regarding the
ECG abnormalities associated with the risk of SCD is limited. One of
the significant findings of our study is a convincing association between
ECG abnormality and risk of SCD among patients with schizophrenia.
Cardiac factors are regarded as the leading cause of SCD; autopsy data
indicate that active coronary lesions were observed in up to 80% of
SCD victims (Priori et al., 2001). Lengthening of the QTc interval has
been recognized as a predictive marker for sudden death in psychiatric
patients due to cardiac arrhythmia (Reilly et al., 2000). In this study, the
types of ECG abnormalities were heterogeneous, including sinus brady-
cardia, myocardial injury, abnormal QRS interval, prolonged QT interval,
beats with aberrant intraventricular conduction, left atrial enlargement,
ST-T abnormality, anteroseptal infarction, A-V block, left ventricular
hypertrophy, and Wolff–Parkinson–White syndrome (type B). Studies
with large samples are needed for investigating whether or not any par-
ticular ECG abnormality is associated with the risk of SCD.
Intriguingly, we found that controls had ECG abnormalities far less
frequently at the latest admission compared with the index admission
(4.4% vs. 10.0%), whereas cases had similar figures (17.4% vs. 18.4%).
Given the temporal consideration, the findings could indicate that ECG
abnormalities are reversible with more active treatment. Nonetheless,
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399
those with persistent ECG abnormalities could have inherently higher
risk for a subsequent SCD; these patients deserve intense clinical atten-
tion and active treatment. Given the non-invasiveness, low cost, and
wide availability of ECG equipment, ECG is a useful tool for helping de-
fine the potential risk for SCD in clinical practice.
4.3. First-generation antipsychotics as risk factors
Since psychotropic medication is essential for the treatment of pa-
tients with schizophrenia, and increased mortality is associated with
delayed treatment and inconsistent drug adherence (Combes and
Feral, 2011), the issue of whether antipsychotic exposure is associated
with SCD is controversial. We demonstrated that patients receiving
first-generation antipsychotics were over five times more likely to die
of SCD, according to the final model (Table 3). Previous studies have
consistently shown that first-generation antipsychotics led to a 2.4 to
3.0-fold increase of SCD, especially butyrophenone antipsychotics and
those with lower potency (Ray et al., 2001; Straus et al., 2004b). Despite
the fact, the dose of antipsychotics was not included in the multivariate
analysis due to the high correlation with the use of antipsychotics. In the
findings from the univariate analysis (Table 2), there was a dose–
response relationship between haloperidol and risk of SCD, which
added some evidence for the association between butyrophenone
antipsychotics and SCD (such as haloperidol). Conversely, this study
suggested that second-generation antipsychotics reduced the risk of
SCD substantially in the univariate analysis but not in the multivariate
analysis. Current evidence is inconsistent regarding the effect of
second-generation antipsychotics on SCD (Kiviniemi et al., 2013;
Rafrafi et al., 2013; Ray et al., 2009). Ray et al. (2009) reported that cur-
rent users of first- and second-generation antipsychotic drugs had a
similar, dose-related increased risk of sudden cardiac death.
In addition, the adverse metabolic effects associated with second-
generation antipsychotics have raised substantial concern, setting the
stage for long-term cardiac mortality (Luft and Taylor, 2006). However,
there seems to be a scarcity of research directly examining whether or
not a suboptimal metabolic profile is associated with SCD in patients
with schizophrenia. In the present study, the participants that died of
SCD did not have worsened metabolic profiles for glucose, cholesterol,
or triglyceride levels (Table 2). One explanation could be that, specifical-
ly in schizophrenia, other competing risk factors may exert a stronger
effect on the risk of SCD.
4.4. Aggression predicts SCD
In patients with schizophrenia, aggression was, in general, associat-
ed with a poor prognosis (Rafrafi et al., 2013; Scigliano and Ronchetti,
2013). Persistent aggression hinders therapeutic alliance, jeopardizing
patients' compliance, insight, social interaction, and consequently,
their repetitive hospital admissions. A previous study demonstrated
Table 3
Multivariate conditional logistic regression of risk factors for sudden cardiac death among
patients with schizophrenia.
Variable Adjusted 95% confidence P value
risk ratio interval
Model 1 (based on the variables at the index admission)
Aggressive behavior 3.99⁎⁎ 1.50–10.64 0.006
Physical disease 2.91⁎⁎ 1.37–6.15 0.005
Model 2 (based on the variables at the latest admission)
Any first-generation antipsychotics 5.13⁎⁎ 1.61–16.40 0.006
Aggressive behavior 3.26⁎ 1.04–10.25 0.043
Abnormal ECG 5.46 ⁎ 1.15–25.97 0.033
ECG: electrocardiogram.
⁎ P b .05.
⁎⁎ P b .01.
400 P.-Y. Hou et al. / Schizophrenia Research 168 (2015) 395–401
that even prodromal aggression was significantly associated with sub-
optimal treatment outcome (Rafrafi et al., 2013). We showed that per-
sistent aggression was specifically associated with SCD. Intriguingly,
the persistent tendency in the presence of aggressive behaviors that
existed either at the index or latest admissions, further implies a notice-
able characteristic that increases the patients' possibility of SCD. The
underlying mechanisms of this novel finding warrant further investiga-
tion. Since loading of antipsychotics remains a viable strategy for violent
patients with schizophrenia (Meyer, 2014), one potential pathway is
that violent patients tended to receive higher doses of antipsychotics
(Appelbaum et al., 1983) or multiple antipsychotics, thus leading to an
escalated risk of SCD.
Despite the finding in this study that was identified to have a
significant risk of aggressive behavior on SCD among patients with
schizophrenia, the association with aggressive behavior should be
interpreted with caution due to the low number in cases and controls.
Future research with a larger, representative sample is required to
delineate the association of aggression and risk of SCD.
4.5. Limitations
Several limitations should be noted when interpreting the findings
of the present study. First, when compared to prior research on
middle-aged and elderly patients (Sweeting et al., 2013), our study
participants were relatively younger and died earlier than reported in
another study of SCD in schizophrenia (Wu et al., 2014). Thus, the gen-
eralizability of the findings in this study could be limited. Moreover, a
relatively short period of follow-up may not fully capture the incidence
of SCD.
Second, despite identifying the association between ECG abnormal-
ity and the risk of SCD, due to the small case number, we could not
further analyze the details of the ECG abnormalities in this study,
which deserve further investigation.
Third, some measures regarding the possible risk of SCD were not
available, such as dietary intake, exercise, and smoking status. Finally,
we explored the factors associated with SCD based on the relevant
variables at the index and latest admissions, respectively. Since the
latest admission of our study participants was still over 4 years earlier
than the SCD event, we were not able to examine the potential, recent
precipitating factors before the SCD event.
4.6. Conclusion
SCD is a not a trivial cause of premature mortality in patients with
schizophrenia. Apart from cardiovascular profiles and antipsychotic ex-
posure, a tendency for physical aggression may be a crucial risk factor
for SCD. Ongoing research should pursue the mechanisms mediating
the association of aggression and SCD in schizophrenia.
Funding/support
This research was supported by grants from the National Science Council, Taiwan
(NSC 102-2628-B-532-001-MY3 and NSC 99-2314-B-532-003-MY3) and Taipei City Hos-
pital (10101-62-055, 10201-62-008, 10301-62-041, and 10401-62-013). The funding
sources had no involvement in the study design, data collection, analysis, interpretation
of data, writing of the report, or the decision to submit the paper for publication.
Author contributions
Drs. Ho, Hung, and Kuo conceived and designed the study. Dr. Ho and Ms. Jhong did
literature search. Dr. Kuo acquired the data. Ms. Jhong performed the statistical analysis.
Drs. Tsai and Chen provided administrative and material support. Drs. Ho, Hung, and
Kuo drafted the manuscript. Drs. Tsai and Chen made critical revisions to the manuscript
for important intellectual content, and Drs. Kuo and Chen supervised the study. Drs.
Galen Chin-Lun Hung and Ping-Yi Ho contributed equally to this article.
Conflicts of interest
The authors declare that they have no competing interests.
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Acknowledgments
The authors thank Yen-Chung Chen, MS, affiliated with the Department of General
Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, for data management and
help with the statistical analyses. Mr. Chen, YC declare that they have no competing
interests.
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