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Risk factors for sudden cardiac death among patients with schizophrenia
Schizophrenia Research 168 (2015) 395–401
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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 Mei-De Branch, Lee General Hospital, Taichung, Taiwan 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 b c
a r t i c l e
i n f o
Article history: Received 18 March 2015 Received in revised form 20 June 2015 Accepted 9 July 2015 Available online 22 July 2015 Keywords: Sudden cardiac death Risk factor Aggression Antipsychotics Schizophrenia
a b s t r a c t Introduction: Patients with schizophrenia suffer from excessive premature mortality, and sudden cardiac death (SCD) is receiving growing attention as a potential cause. Aim: The present study investigated the incidence of SCD and its risk factors in a large schizophrenia cohort. Methods: We enrolled a consecutive series of 8264 patients diagnosed with schizophrenia (according to DSM-IIIR 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 standardized mortality ratio (SMR) for SCD was estimated. The cases were matched with controls randomly selected using risk-set sampling in a 1:2 ratio. A standardized chart review process was used to collect sociodemographic and clinical characteristics and the prescribed drugs for each study subject. Multivariate conditional logistic regression analysis was used to identify correlates of SCD at the index admission and the latest admission. 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 decade (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 explanation for their shorter life expectancy is a tendency toward unnatural 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: [email protected] (C.-J. Kuo).
http://dx.doi.org/10.1016/j.schres.2015.07.015 0920-9964/© 2015 Elsevier B.V. All rights reserved.
(Crump et al., 2013; Saha et al., 2007; Sweeting et al., 2013). Nonetheless, two-thirds of the premature deaths among patients with schizophrenia 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 account for over half of the cases (Ifteni et al., 2014). SCD is typically defined 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 general population are not well established, but age, smoking, metabolic profile (e.g., hyperlipidemia, hypertension, glucose intolerance, obesity),
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cardiac conditions (e.g., tachycardia, left ventricular hypertrophy, intraventricular 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 comprehensive exploration of potential risk factors, including demographic characteristics, cardiovascular diseases, psychopathology, and laboratory 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, laboratory markers, and electrocardiography findings.
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 obtained 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 potentially much less sensitivity to bias from exposure-related loss-tofollow-up, as noted by epidemiologists (Greenland and Thomas, 1982; Miettinen, 1976). We used this methodology to select controls in previous 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 hospitalization during the study period. Additionally, controls were selected from cohort patients who were alive at the time of death of the corresponding 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 unavailable 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
2. Methods
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 underlying 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 subacute 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.
A semi-structured form was used for any inpatient who was admitted to the Taipei City Psychiatric Center since 1980 (Kuo et al., 2011). The form collected clinical information and contained over 95 items including sociodemographic information and a detailed psychiatric evaluation, 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 semistructured 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 electrocardiography (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 structured concept form comprising 115 items for helping the review process. Typically, for each patient, 40 min were required to obtain the information 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 laboratory data related to the index and latest (most recent) hospital admissions, 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 example, 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.
2.3. Nested case–control study
2.5. Statistical analyses
Derived from the study cohort (N = 8264), we conducted a nested case–control study to explore potential risk factors associated with
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
2.1. Study population We enrolled patients with schizophrenia who were consecutively admitted to a psychiatric service center in northern Taiwan from January 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 psychiatrist 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
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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 personyears) 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 marital status, living with family, educational level, employment, and socioeconomic 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 (n = 53)
Controls (n = 103)
Index admission Gender Male Female Married Living with family Education, N12 years Employed Hollingshead socio-economic status, class IV or V
n (%)
n (%)
29 (54.7) 24 (45.3) 13 (24.5) 42 (79.3) 9 (17.7) 4 (7.6) 51 (100.0)
Age, y/o The onset of schizophrenia, y/o The duration from the onset to the index admission, years
57 (55.3) 46 (44.7) 33 (32.7) 78 (75.7) 23 (22.8) 16 (15.7) 96 (95.1)
Mean (SD)
Mean (SD)
46.0 (15.8) 30.1 (13.5) 15.1 (12.2)
44.1 (15.5) 32.6 (13.3) 11.5 (11.6)
Unadjusted risk ratioa
95% CI
P
… … 0.59 1.30 0.67 0.45 –
… … 0.26–1.35 0.51–3.35 0.27–1.70 0.14–1.44 –
… … 0.211 0.582 0.400 0.180 –
1.10 0.97 1.04
0.98–1.24 0.94–1.01 1.00–1.08
0.113 0.153 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 infarction (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 differences 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 proportion 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
Comorbidity Substance use disorders Psychosis-related symptoms Auditory hallucination Visual hallucination Persecutory delusion Behaviors Suicide behavior Behaving aggressively to people Abnormal ECG Physical diseases Cardiovascular diseases Diabetes Any antidepressant Antipsychotic used Both FGA and SGA Only FGA used Only SGA used
Index admission
Latest admission
Cases (n = 53)
Controls (n = 103)
n (%)
n (%)
Unadjusted risk ratio
P
Cases (n = 53)
Controls (n = 103)
n (%)
n (%)
Unadjusted risk ratio
P
4 (7.6)
1 (1.0)
8.00
0.063
2 (3.8)
2 (1.9)
2.00
0.488
44 (83.0) 13 (24.5) 38 (71.7)
77 (74.8) 21 (20.4) 74 (71.8)
1.63 1.32 0.98
0.261 0.518 0.952
41 (77.4) 14 (26.4) 39 (73.6)
64 (62.1) 14 (13.6) 65 (63.1)
1.95 2.24 1.62
0.076 0.058 0.207
0 (–) 17 (32.1) 9 (18.4) 33 (62.3) 7 (13.2) 3 (5.7) 2 (3.8) 51 (96.2) 0 (–) 43 (81.1) 8 (15.1)
1 (1.0) 13 (12.6) 9 (10.0) 38 (36.9) 12 (11.7) 5 (4.9) 6 (5.8) 96 (93.2) 1 (1.0) 76 (73.8) 19 (18.5)
0.00 3.51⁎⁎ 2.28 2.85⁎⁎
0.995 0.007 0.182 0.004 0.845 0.692 0.620 0.459 0.995 0.203 0.471
1 (1.9) 18 (34.0) 8 (17.4) 31 (58.5) 7 (13.2) 3 (5.7) 4 (7.6) 51 (96.2) 0 (–) 41 (77.4) 10 (18.9)
1 (1.0) 12 (11.7) 4 (4.4) 44 (42.7) 14 (13.6) 7 (6.8) 8 (7.8) 95 (92.2) 2 (1.9) 59 (57.3) 34 (33.0)
2.00 4.38⁎⁎ 4.39⁎ 1.88 0.90 1.11 0.93 2.30 0.00 3.78⁎ 0.35⁎
0.624 0.002 0.033 0.076 0.850 0.895 0.916 0.328 0.992 0.006 0.031
Mean (SD) Antipsychotic dose (unit as the defined daily dose, DDD) Haloperidol 0.52 (0.7) Risperidone 0.05 (0.2) Body mass index (BMI) 24.3 (5.2) Laboratory marker Fasting glucose (mg/dL) 100.6 (24.2) Serum cholesterol (mg/dL) 194.7 (42.0) Serum triglyceride (mg/dL) 132.9 (68.1) Albumin (g/dL) 4.2 (0.4) Sodium (Na) (mmol/L) 142.9 (3.6) Potassium (K) (mmol/L) 4.0 (0.4) Leucocytes (×103/μL) 7515.8 (3144.7) Hemoglobin (mg/dL) 13.7 (1.7)
1.12 1.36 0.67 1.86 0.00 1.93 0.66
Mean (SD)
Mean (SD)
Mean (SD)
0.38 (0.7) 0.07 (0.2) 22.8 (3.9)
1.28 0.58 1.09
0.2695 0.5333 0.059
0.51 (0.8) 0.06 (0.2) 24.5 (5.4)
0.23 (0.5) 0.14 (0.3) 23.2 (3.9)
1.86⁎ 0.31 1.08
0.019 0.126 0.081
102.3 (40.2) 188.9 (38.3) 114.4 (55.8) 4.2 (0.4) 141.8 (3.0) 4.0 (0.4) 6657.8 (2658.7) 13.6 (2.0)
1.00 1.00 1.01 0.95 1.15⁎ 1.44 1.00 1.12
0.790 0.443 0.135 0.906 0.047 0.413 0.056 0.356
103.2 (30.3) 193.5 (41.9) 126.3 (69.1) 4.2 (0.4) 143.0 (3.7) 4.0 (0.4) 7319.5 (3275.4) 13.6 (1.6)
102.0 (43.1) 188.4 (40.0) 124.1 (71.7) 4.2 (0.5) 143.0 (31.2) 5.1 (10.5) 6744.6 (2803.4) 16.3 (27.5)
1.00 1.00 1.00 0.90 1.00 0.94 1.00 0.99
0.909 0.427 0.465 0.793 0.988 0.822 0.174 0.675
FGA: first-generation antipsychotics; SGA: second-generation antipsychotics; ECG: electrocardiogram. ⁎ P b 0.05. ⁎⁎ P b 0.01.
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(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 difference 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 admission. 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 elevated 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 exceptionally 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 conventional 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 bradycardia, 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 particular 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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those with persistent ECG abnormalities could have inherently higher risk for a subsequent SCD; these patients deserve intense clinical attention and active treatment. Given the non-invasiveness, low cost, and wide availability of ECG equipment, ECG is a useful tool for helping define 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 patients 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 current 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 secondgeneration 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, specifically 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, associated 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 risk ratio
95% confidence interval
Model 1 (based on the variables at the index admission) Aggressive behavior 3.99⁎⁎ 1.50–10.64 Physical disease 2.91⁎⁎ 1.37–6.15 Model 2 (based on the variables at the latest admission) Any first-generation antipsychotics 5.13⁎⁎ 1.61–16.40 Aggressive behavior 3.26⁎ 1.04–10.25 ⁎ Abnormal ECG 5.46 1.15–25.97 ECG: electrocardiogram. ⁎ P b .05. ⁎⁎ P b .01.
P value
0.006 0.005 0.006 0.043 0.033
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that even prodromal aggression was significantly associated with suboptimal treatment outcome (Rafrafi et al., 2013). We showed that persistent 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 noticeable characteristic that increases the patients' possibility of SCD. The underlying mechanisms of this novel finding warrant further investigation. 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 generalizability 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 abnormality 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 exposure, 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 Hospital (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.
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.
References Appelbaum, P.S., Jackson, A.H., Shader, R.I., 1983. Psychiatrists' responses to violence: pharmacologic management of psychiatric inpatients. Am. J. Psychiatry 140 (3), 301–304. Chugh, S.S., Jui, J., Gunson, K., Stecker, E.C., John, B.T., Thompson, B., Ilias, N., Vickers, C., Dogra, V., Daya, M., Kron, J., Zheng, Z.J., Mensah, G., McAnulty, J., 2004. Current burden of sudden cardiac death: multiple source surveillance versus retrospective death certificate-based review in a large U.S. community. J. Am. Coll. Cardiol. 44 (6), 1268–1275. Chute, D., Grove, C., Rajasekhara, B., Smialek, J.E., 1999. Schizophrenia and sudden death: a medical examiner case study. Am. J. Forensic Med. Pathol. 20 (2), 131–135. Cohen, H., Loewenthal, U., Matar, M., Kotler, M., 2001. Association of autonomic dysfunction and clozapine. Heart rate variability and risk for sudden death in patients with schizophrenia on long-term psychotropic medication. Br. J. Psychiatry 179, 167–171. Combes, C., Feral, F., 2011. Drug compliance and health locus of control in schizophrenia. Encéphale 37 (Suppl. 1), S11–S18. Crump, C., Winkleby, M.A., Sundquist, K., Sundquist, J., 2013. Comorbidities and mortality in persons with schizophrenia: a Swedish national cohort study. Am. J. Psychiatry 170 (3), 324–333. Davidson, M., 2002. Risk of cardiovascular disease and sudden death in schizophrenia. J. Clin. Psychiatry 63 (Suppl. 9), 5–11. Girardin, F.R., Gex-Fabry, M., Berney, P., Shah, D., Gaspoz, J.M., Dayer, P., 2013. Druginduced long QT in adult psychiatric inpatients: the 5-year cross-sectional ECG Screening Outcome in Psychiatry study. Am. J. Psychiatry 170 (12), 1468–1476. Glassman, A.H., Bigger Jr., J.T., 2001. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am. J. Psychiatry 158 (11), 1774–1782. Greenland, S., 2008. Case–control studies. In: Rothman, K.J., Greenland, S., Lash, T.L. (Eds.), Modern Epidemiology, Third ed. Lippincott Williams & Wilkins, Philadelphia, pp. 111–127. Greenland, S., Thomas, D.C., 1982. On the need for the rare disease assumption in case– control studies. Am. J. Epidemiol. 116 (3), 547–553. Hollingshead, A., Rhdlich, F., 1958. Social Class and Mental Illness. Wiley, New York, NY. Ifteni, P., Correll, C.U., Burtea, V., Kane, J.M., Manu, P., 2014. Sudden unexpected death in schizophrenia: autopsy findings in psychiatric inpatients. Schizophr. Res. 155 (1–3), 72–76. Kiviniemi, M., Suvisaari, J., Koivumaa-Honkanen, H., Hakkinen, U., Isohanni, M., Hakko, H., 2013. Antipsychotics and mortality in first-onset schizophrenia: prospective Finnish register study with 5-year follow-up. Schizophr. Res. 150 (1), 274–280. Kuo, C.J., Tsai, S.Y., Liao, Y.T., Conwell, Y., Lin, S.K., Chang, C.L., Chen, C.C., Chen, W.J., 2011. Risk and protective factors for suicide among patients with methamphetamine dependence: a nested case–control study. J. Clin. Psychiatry 72 (4), 487–493. Kuo, C.J., Tsai, S.Y., Liao, Y.T., Conwell, Y., Lee, W.C., Huang, M.C., Lin, S.K., Chen, C.C., Chen, W.J., 2012. Elevated aspartate and alanine aminotransferase levels and natural death among patients with methamphetamine dependence. PLoS One 7 (1), e29325. Laursen, T.M., Munk-Olsen, T., Gasse, C., 2011. Chronic somatic comorbidity and excess mortality due to natural causes in persons with schizophrenia or bipolar affective disorder. PLoS One 6 (9), e24597. Luft, B., Taylor, D., 2006. A review of atypical antipsychotic drugs versus conventional medication in schizophrenia. Expert. Opin. Pharmacother. 7 (13), 1739–1748. Meyer, J.M., 2014. A rational approach to employing high plasma levels of antipsychotics for violence associated with schizophrenia: case vignettes. CNS Spectr. 19 (5), 432–438. Miettinen, O., 1976. Estimability and estimation in case-referent studies. Am. J. Epidemiol. 103 (2), 226–235. Newcomer, J.W., 2007. Antipsychotic medications: metabolic and cardiovascular risk. J. Clin. Psychiatry 68 (Suppl. 4), 8–13. Pan, C.H., Jhong, J.R., Tsai, S.Y., Lin, S.K., Chen, C.C., Kuo, C.J., 2014. Excessive suicide mortality and risk factors for suicide among patients with heroin dependence. Drug Alcohol Depend. 145, 224–230. Priori, S.G., Aliot, E., Blomstrom-Lundqvist, C., Bossaert, L., Breithardt, G., Brugada, P., Camm, A.J., Cappato, R., Cobbe, S.M., Di Mario, C., Maron, B.J., McKenna, W.J., Pedersen, A.K., Ravens, U., Schwartz, P.J., Trusz-Gluza, M., Vardas, P., Wellens, H.J., Zipes, D.P., 2001. Task force on sudden cardiac death of the European Society of Cardiology. Eur. Heart J. 22 (16), 1374–1450. Rafrafi, R., Bahrini, L., Robbana, L., Bergaoui, H., Melki, W., El Hechmi, Z., 2013. Violence in schizophrenia: a study of 60 cases. Tunis. Med. 91 (12), 729–734. Ray, W.A., Meredith, S., Thapa, P.B., Meador, K.G., Hall, K., Murray, K.T., 2001. Antipsychotics and the risk of sudden cardiac death. Arch. Gen. Psychiatry 58 (12), 1161–1167. Ray, W.A., Chung, C.P., Murray, K.T., Hall, K., Stein, C.M., 2009. Atypical antipsychotic drugs and the risk of sudden cardiac death. N. Engl. J. Med. 360 (3), 225–235. Reilly, J.G., Ayis, S.A., Ferrier, I.N., Jones, S.J., Thomas, S.H., 2000. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 355 (9209), 1048–1052. Saha, S., Chant, D., McGrath, J., 2007. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch. Gen. Psychiatry 64 (10), 1123–1131.
P.-Y. Hou et al. / Schizophrenia Research 168 (2015) 395–401 Scigliano, G., Ronchetti, G., 2013. Antipsychotic-induced metabolic and cardiovascular side effects in schizophrenia: a novel mechanistic hypothesis. CNS Drugs 27 (4), 249–257. Straus, S.M., Bleumink, G.S., Dieleman, J.P., van der Lei, J., Stricker, B.H., Sturkenboom, M.C., 2004a. The incidence of sudden cardiac death in the general population. J. Clin. Epidemiol. 57 (1), 98–102. Straus, S.M., Bleumink, G.S., Dieleman, J.P., van der Lei, J., t Jong, G.W., Kingma, J.H., Sturkenboom, M.C., Stricker, B.H., 2004b. Antipsychotics and the risk of sudden cardiac death. Arch. Intern. Med. 164 (12), 1293–1297. Suvisaari, J., Perala, J., Saarni, S.I., Kattainen, A., Lonnqvist, J., Reunanen, A., 2010. Coronary heart disease and cardiac conduction abnormalities in persons with psychotic disorders in a general population. Psychiatry Res. 175 (1–2), 126–132.
401
Sweeting, J., Duflou, J., Semsarian, C., 2013. Postmortem analysis of cardiovascular deaths in schizophrenia: a 10-year review. Schizophr. Res. 150 (2–3), 398–403. WHO Collaborating Centre for Drug Statistic Methodology, 2009. ATC Index with DDDs. WHO, Oslo. Wu, Y.H., Lai, C.Y., Chang, Y.S., 2014. Antipsychotic polypharmacy among elderly patients with schizophrenia and dementia during hospitalization at a Taiwanese psychiatric hospital. Psychogeriatrics 2015 (1), 7–13. Zheng, Z.J., Croft, J.B., Giles, W.H., Mensah, G.A., 2001. Sudden cardiac death in the United States, 1989 to 1998. Circulation 104 (18), 2158–2163.
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Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
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 Mei-De Branch, Lee General Hospital, Taichung, Taiwan 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 b c
a r t i c l e
i n f o
Article history: Received 18 March 2015 Received in revised form 20 June 2015 Accepted 9 July 2015 Available online 22 July 2015 Keywords: Sudden cardiac death Risk factor Aggression Antipsychotics Schizophrenia
a b s t r a c t Introduction: Patients with schizophrenia suffer from excessive premature mortality, and sudden cardiac death (SCD) is receiving growing attention as a potential cause. Aim: The present study investigated the incidence of SCD and its risk factors in a large schizophrenia cohort. Methods: We enrolled a consecutive series of 8264 patients diagnosed with schizophrenia (according to DSM-IIIR 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 standardized mortality ratio (SMR) for SCD was estimated. The cases were matched with controls randomly selected using risk-set sampling in a 1:2 ratio. A standardized chart review process was used to collect sociodemographic and clinical characteristics and the prescribed drugs for each study subject. Multivariate conditional logistic regression analysis was used to identify correlates of SCD at the index admission and the latest admission. 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 decade (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 explanation for their shorter life expectancy is a tendency toward unnatural 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: [email protected] (C.-J. Kuo).
http://dx.doi.org/10.1016/j.schres.2015.07.015 0920-9964/© 2015 Elsevier B.V. All rights reserved.
(Crump et al., 2013; Saha et al., 2007; Sweeting et al., 2013). Nonetheless, two-thirds of the premature deaths among patients with schizophrenia 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 account for over half of the cases (Ifteni et al., 2014). SCD is typically defined 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 general population are not well established, but age, smoking, metabolic profile (e.g., hyperlipidemia, hypertension, glucose intolerance, obesity),
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cardiac conditions (e.g., tachycardia, left ventricular hypertrophy, intraventricular 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 comprehensive exploration of potential risk factors, including demographic characteristics, cardiovascular diseases, psychopathology, and laboratory 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, laboratory markers, and electrocardiography findings.
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 obtained 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 potentially much less sensitivity to bias from exposure-related loss-tofollow-up, as noted by epidemiologists (Greenland and Thomas, 1982; Miettinen, 1976). We used this methodology to select controls in previous 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 hospitalization during the study period. Additionally, controls were selected from cohort patients who were alive at the time of death of the corresponding 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 unavailable 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
2. Methods
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 underlying 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 subacute 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.
A semi-structured form was used for any inpatient who was admitted to the Taipei City Psychiatric Center since 1980 (Kuo et al., 2011). The form collected clinical information and contained over 95 items including sociodemographic information and a detailed psychiatric evaluation, 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 semistructured 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 electrocardiography (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 structured concept form comprising 115 items for helping the review process. Typically, for each patient, 40 min were required to obtain the information 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 laboratory data related to the index and latest (most recent) hospital admissions, 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 example, 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.
2.3. Nested case–control study
2.5. Statistical analyses
Derived from the study cohort (N = 8264), we conducted a nested case–control study to explore potential risk factors associated with
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
2.1. Study population We enrolled patients with schizophrenia who were consecutively admitted to a psychiatric service center in northern Taiwan from January 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 psychiatrist 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
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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 personyears) 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 marital status, living with family, educational level, employment, and socioeconomic 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 (n = 53)
Controls (n = 103)
Index admission Gender Male Female Married Living with family Education, N12 years Employed Hollingshead socio-economic status, class IV or V
n (%)
n (%)
29 (54.7) 24 (45.3) 13 (24.5) 42 (79.3) 9 (17.7) 4 (7.6) 51 (100.0)
Age, y/o The onset of schizophrenia, y/o The duration from the onset to the index admission, years
57 (55.3) 46 (44.7) 33 (32.7) 78 (75.7) 23 (22.8) 16 (15.7) 96 (95.1)
Mean (SD)
Mean (SD)
46.0 (15.8) 30.1 (13.5) 15.1 (12.2)
44.1 (15.5) 32.6 (13.3) 11.5 (11.6)
Unadjusted risk ratioa
95% CI
P
… … 0.59 1.30 0.67 0.45 –
… … 0.26–1.35 0.51–3.35 0.27–1.70 0.14–1.44 –
… … 0.211 0.582 0.400 0.180 –
1.10 0.97 1.04
0.98–1.24 0.94–1.01 1.00–1.08
0.113 0.153 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 infarction (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 differences 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 proportion 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
Comorbidity Substance use disorders Psychosis-related symptoms Auditory hallucination Visual hallucination Persecutory delusion Behaviors Suicide behavior Behaving aggressively to people Abnormal ECG Physical diseases Cardiovascular diseases Diabetes Any antidepressant Antipsychotic used Both FGA and SGA Only FGA used Only SGA used
Index admission
Latest admission
Cases (n = 53)
Controls (n = 103)
n (%)
n (%)
Unadjusted risk ratio
P
Cases (n = 53)
Controls (n = 103)
n (%)
n (%)
Unadjusted risk ratio
P
4 (7.6)
1 (1.0)
8.00
0.063
2 (3.8)
2 (1.9)
2.00
0.488
44 (83.0) 13 (24.5) 38 (71.7)
77 (74.8) 21 (20.4) 74 (71.8)
1.63 1.32 0.98
0.261 0.518 0.952
41 (77.4) 14 (26.4) 39 (73.6)
64 (62.1) 14 (13.6) 65 (63.1)
1.95 2.24 1.62
0.076 0.058 0.207
0 (–) 17 (32.1) 9 (18.4) 33 (62.3) 7 (13.2) 3 (5.7) 2 (3.8) 51 (96.2) 0 (–) 43 (81.1) 8 (15.1)
1 (1.0) 13 (12.6) 9 (10.0) 38 (36.9) 12 (11.7) 5 (4.9) 6 (5.8) 96 (93.2) 1 (1.0) 76 (73.8) 19 (18.5)
0.00 3.51⁎⁎ 2.28 2.85⁎⁎
0.995 0.007 0.182 0.004 0.845 0.692 0.620 0.459 0.995 0.203 0.471
1 (1.9) 18 (34.0) 8 (17.4) 31 (58.5) 7 (13.2) 3 (5.7) 4 (7.6) 51 (96.2) 0 (–) 41 (77.4) 10 (18.9)
1 (1.0) 12 (11.7) 4 (4.4) 44 (42.7) 14 (13.6) 7 (6.8) 8 (7.8) 95 (92.2) 2 (1.9) 59 (57.3) 34 (33.0)
2.00 4.38⁎⁎ 4.39⁎ 1.88 0.90 1.11 0.93 2.30 0.00 3.78⁎ 0.35⁎
0.624 0.002 0.033 0.076 0.850 0.895 0.916 0.328 0.992 0.006 0.031
Mean (SD) Antipsychotic dose (unit as the defined daily dose, DDD) Haloperidol 0.52 (0.7) Risperidone 0.05 (0.2) Body mass index (BMI) 24.3 (5.2) Laboratory marker Fasting glucose (mg/dL) 100.6 (24.2) Serum cholesterol (mg/dL) 194.7 (42.0) Serum triglyceride (mg/dL) 132.9 (68.1) Albumin (g/dL) 4.2 (0.4) Sodium (Na) (mmol/L) 142.9 (3.6) Potassium (K) (mmol/L) 4.0 (0.4) Leucocytes (×103/μL) 7515.8 (3144.7) Hemoglobin (mg/dL) 13.7 (1.7)
1.12 1.36 0.67 1.86 0.00 1.93 0.66
Mean (SD)
Mean (SD)
Mean (SD)
0.38 (0.7) 0.07 (0.2) 22.8 (3.9)
1.28 0.58 1.09
0.2695 0.5333 0.059
0.51 (0.8) 0.06 (0.2) 24.5 (5.4)
0.23 (0.5) 0.14 (0.3) 23.2 (3.9)
1.86⁎ 0.31 1.08
0.019 0.126 0.081
102.3 (40.2) 188.9 (38.3) 114.4 (55.8) 4.2 (0.4) 141.8 (3.0) 4.0 (0.4) 6657.8 (2658.7) 13.6 (2.0)
1.00 1.00 1.01 0.95 1.15⁎ 1.44 1.00 1.12
0.790 0.443 0.135 0.906 0.047 0.413 0.056 0.356
103.2 (30.3) 193.5 (41.9) 126.3 (69.1) 4.2 (0.4) 143.0 (3.7) 4.0 (0.4) 7319.5 (3275.4) 13.6 (1.6)
102.0 (43.1) 188.4 (40.0) 124.1 (71.7) 4.2 (0.5) 143.0 (31.2) 5.1 (10.5) 6744.6 (2803.4) 16.3 (27.5)
1.00 1.00 1.00 0.90 1.00 0.94 1.00 0.99
0.909 0.427 0.465 0.793 0.988 0.822 0.174 0.675
FGA: first-generation antipsychotics; SGA: second-generation antipsychotics; ECG: electrocardiogram. ⁎ P b 0.05. ⁎⁎ P b 0.01.
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 difference 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 admission. 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 elevated 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 exceptionally 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 conventional 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 bradycardia, 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 particular 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,
399
those with persistent ECG abnormalities could have inherently higher risk for a subsequent SCD; these patients deserve intense clinical attention and active treatment. Given the non-invasiveness, low cost, and wide availability of ECG equipment, ECG is a useful tool for helping define 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 patients 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 current 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 secondgeneration 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, specifically 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, associated 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 risk ratio
95% confidence interval
Model 1 (based on the variables at the index admission) Aggressive behavior 3.99⁎⁎ 1.50–10.64 Physical disease 2.91⁎⁎ 1.37–6.15 Model 2 (based on the variables at the latest admission) Any first-generation antipsychotics 5.13⁎⁎ 1.61–16.40 Aggressive behavior 3.26⁎ 1.04–10.25 ⁎ Abnormal ECG 5.46 1.15–25.97 ECG: electrocardiogram. ⁎ P b .05. ⁎⁎ P b .01.
P value
0.006 0.005 0.006 0.043 0.033
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that even prodromal aggression was significantly associated with suboptimal treatment outcome (Rafrafi et al., 2013). We showed that persistent 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 noticeable characteristic that increases the patients' possibility of SCD. The underlying mechanisms of this novel finding warrant further investigation. 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 generalizability 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 abnormality 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 exposure, 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 Hospital (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.
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.
References Appelbaum, P.S., Jackson, A.H., Shader, R.I., 1983. Psychiatrists' responses to violence: pharmacologic management of psychiatric inpatients. Am. J. Psychiatry 140 (3), 301–304. Chugh, S.S., Jui, J., Gunson, K., Stecker, E.C., John, B.T., Thompson, B., Ilias, N., Vickers, C., Dogra, V., Daya, M., Kron, J., Zheng, Z.J., Mensah, G., McAnulty, J., 2004. Current burden of sudden cardiac death: multiple source surveillance versus retrospective death certificate-based review in a large U.S. community. J. Am. Coll. Cardiol. 44 (6), 1268–1275. Chute, D., Grove, C., Rajasekhara, B., Smialek, J.E., 1999. Schizophrenia and sudden death: a medical examiner case study. Am. J. Forensic Med. Pathol. 20 (2), 131–135. Cohen, H., Loewenthal, U., Matar, M., Kotler, M., 2001. Association of autonomic dysfunction and clozapine. Heart rate variability and risk for sudden death in patients with schizophrenia on long-term psychotropic medication. Br. J. Psychiatry 179, 167–171. Combes, C., Feral, F., 2011. Drug compliance and health locus of control in schizophrenia. Encéphale 37 (Suppl. 1), S11–S18. Crump, C., Winkleby, M.A., Sundquist, K., Sundquist, J., 2013. Comorbidities and mortality in persons with schizophrenia: a Swedish national cohort study. Am. J. Psychiatry 170 (3), 324–333. Davidson, M., 2002. Risk of cardiovascular disease and sudden death in schizophrenia. J. Clin. Psychiatry 63 (Suppl. 9), 5–11. Girardin, F.R., Gex-Fabry, M., Berney, P., Shah, D., Gaspoz, J.M., Dayer, P., 2013. Druginduced long QT in adult psychiatric inpatients: the 5-year cross-sectional ECG Screening Outcome in Psychiatry study. Am. J. Psychiatry 170 (12), 1468–1476. Glassman, A.H., Bigger Jr., J.T., 2001. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am. J. Psychiatry 158 (11), 1774–1782. Greenland, S., 2008. Case–control studies. In: Rothman, K.J., Greenland, S., Lash, T.L. (Eds.), Modern Epidemiology, Third ed. Lippincott Williams & Wilkins, Philadelphia, pp. 111–127. Greenland, S., Thomas, D.C., 1982. On the need for the rare disease assumption in case– control studies. Am. J. Epidemiol. 116 (3), 547–553. Hollingshead, A., Rhdlich, F., 1958. Social Class and Mental Illness. Wiley, New York, NY. Ifteni, P., Correll, C.U., Burtea, V., Kane, J.M., Manu, P., 2014. Sudden unexpected death in schizophrenia: autopsy findings in psychiatric inpatients. Schizophr. Res. 155 (1–3), 72–76. Kiviniemi, M., Suvisaari, J., Koivumaa-Honkanen, H., Hakkinen, U., Isohanni, M., Hakko, H., 2013. Antipsychotics and mortality in first-onset schizophrenia: prospective Finnish register study with 5-year follow-up. Schizophr. Res. 150 (1), 274–280. Kuo, C.J., Tsai, S.Y., Liao, Y.T., Conwell, Y., Lin, S.K., Chang, C.L., Chen, C.C., Chen, W.J., 2011. Risk and protective factors for suicide among patients with methamphetamine dependence: a nested case–control study. J. Clin. Psychiatry 72 (4), 487–493. Kuo, C.J., Tsai, S.Y., Liao, Y.T., Conwell, Y., Lee, W.C., Huang, M.C., Lin, S.K., Chen, C.C., Chen, W.J., 2012. Elevated aspartate and alanine aminotransferase levels and natural death among patients with methamphetamine dependence. PLoS One 7 (1), e29325. Laursen, T.M., Munk-Olsen, T., Gasse, C., 2011. Chronic somatic comorbidity and excess mortality due to natural causes in persons with schizophrenia or bipolar affective disorder. PLoS One 6 (9), e24597. Luft, B., Taylor, D., 2006. A review of atypical antipsychotic drugs versus conventional medication in schizophrenia. Expert. Opin. Pharmacother. 7 (13), 1739–1748. Meyer, J.M., 2014. A rational approach to employing high plasma levels of antipsychotics for violence associated with schizophrenia: case vignettes. CNS Spectr. 19 (5), 432–438. Miettinen, O., 1976. Estimability and estimation in case-referent studies. Am. J. Epidemiol. 103 (2), 226–235. Newcomer, J.W., 2007. Antipsychotic medications: metabolic and cardiovascular risk. J. Clin. Psychiatry 68 (Suppl. 4), 8–13. Pan, C.H., Jhong, J.R., Tsai, S.Y., Lin, S.K., Chen, C.C., Kuo, C.J., 2014. Excessive suicide mortality and risk factors for suicide among patients with heroin dependence. Drug Alcohol Depend. 145, 224–230. Priori, S.G., Aliot, E., Blomstrom-Lundqvist, C., Bossaert, L., Breithardt, G., Brugada, P., Camm, A.J., Cappato, R., Cobbe, S.M., Di Mario, C., Maron, B.J., McKenna, W.J., Pedersen, A.K., Ravens, U., Schwartz, P.J., Trusz-Gluza, M., Vardas, P., Wellens, H.J., Zipes, D.P., 2001. Task force on sudden cardiac death of the European Society of Cardiology. Eur. Heart J. 22 (16), 1374–1450. Rafrafi, R., Bahrini, L., Robbana, L., Bergaoui, H., Melki, W., El Hechmi, Z., 2013. Violence in schizophrenia: a study of 60 cases. Tunis. Med. 91 (12), 729–734. Ray, W.A., Meredith, S., Thapa, P.B., Meador, K.G., Hall, K., Murray, K.T., 2001. Antipsychotics and the risk of sudden cardiac death. Arch. Gen. Psychiatry 58 (12), 1161–1167. Ray, W.A., Chung, C.P., Murray, K.T., Hall, K., Stein, C.M., 2009. Atypical antipsychotic drugs and the risk of sudden cardiac death. N. Engl. J. Med. 360 (3), 225–235. Reilly, J.G., Ayis, S.A., Ferrier, I.N., Jones, S.J., Thomas, S.H., 2000. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 355 (9209), 1048–1052. Saha, S., Chant, D., McGrath, J., 2007. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch. Gen. Psychiatry 64 (10), 1123–1131.
P.-Y. Hou et al. / Schizophrenia Research 168 (2015) 395–401 Scigliano, G., Ronchetti, G., 2013. Antipsychotic-induced metabolic and cardiovascular side effects in schizophrenia: a novel mechanistic hypothesis. CNS Drugs 27 (4), 249–257. Straus, S.M., Bleumink, G.S., Dieleman, J.P., van der Lei, J., Stricker, B.H., Sturkenboom, M.C., 2004a. The incidence of sudden cardiac death in the general population. J. Clin. Epidemiol. 57 (1), 98–102. Straus, S.M., Bleumink, G.S., Dieleman, J.P., van der Lei, J., t Jong, G.W., Kingma, J.H., Sturkenboom, M.C., Stricker, B.H., 2004b. Antipsychotics and the risk of sudden cardiac death. Arch. Intern. Med. 164 (12), 1293–1297. Suvisaari, J., Perala, J., Saarni, S.I., Kattainen, A., Lonnqvist, J., Reunanen, A., 2010. Coronary heart disease and cardiac conduction abnormalities in persons with psychotic disorders in a general population. Psychiatry Res. 175 (1–2), 126–132.
401
Sweeting, J., Duflou, J., Semsarian, C., 2013. Postmortem analysis of cardiovascular deaths in schizophrenia: a 10-year review. Schizophr. Res. 150 (2–3), 398–403. WHO Collaborating Centre for Drug Statistic Methodology, 2009. ATC Index with DDDs. WHO, Oslo. Wu, Y.H., Lai, C.Y., Chang, Y.S., 2014. Antipsychotic polypharmacy among elderly patients with schizophrenia and dementia during hospitalization at a Taiwanese psychiatric hospital. Psychogeriatrics 2015 (1), 7–13. Zheng, Z.J., Croft, J.B., Giles, W.H., Mensah, G.A., 2001. Sudden cardiac death in the United States, 1989 to 1998. Circulation 104 (18), 2158–2163.