Leading causes of death among decedents with

Schizophrenia Research 197 (2018) 116–123

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Leading causes of death among decedents with mention of schizophrenia on the death certificates in the United States Jin-Jia Lin a,b, Fu-Weng Liang c, Chung-Yi Li c,d, Tsung-Hsueh Lu c,⁎ a

The Department of Psychiatry, Chi Mei Medical Center, Tainan, Taiwan Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan The NCKU Center for Health Data and Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan d Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan b c

a r t i c l e

i n f o

Article history: Received 18 February 2017 Received in revised form 2 December 2017 Accepted 17 January 2018 Available online 1 February 2018 Keywords: Death certificate Multiple causes of death Leading causes of death Schizophrenia

a b s t r a c t Background: Little is known about the changes in the ranking of leading cause of death (COD) among people died with schizophrenia across years in the United States (U.S.). This study aims to determine the ranking of leading COD among U.S. decedents with mention of schizophrenia by age from 2000 to 2015. Methods: The mortality multiple COD files maintained by the National Center for Health Statistics were used to identify decedents aged 15 years old and above with mention of schizophrenia anywhere on the death certificates to determine the number and proportion of deaths attributed to various underlying CODs. Results: Of 13,289, 13,655, 14,135, and 15,033 people who died in 2000–2003, 2004–2007, 2008-2011and 2012–2015 with mention of schizophrenia, similar to all decedents, heart disease and cancer was the first and the second leading COD throughout the study years. Schizophrenia ranked the third in most years except in 2004–2007. The first leading COD for decedents with mention of schizophrenia aged 15–24, 25–44, 45–64, 65–74, and 75+ years old in 2012–2015 was suicide, accidents, heart disease, heart disease, and Alzheimer's disease and related dementia, respectively. Nevertheless, it was accidents, accidents, cancer, cancer, and heart disease, respectively for all decedents. Conclusion: The ranking of leading CODs among U.S. decedents with mention of schizophrenia changed across years and differed from all decedents by age, which suggest that different interventions should be designed accordingly. © 2018 Elsevier B.V. All rights reserved.

1. Introduction Systematic reviews (Saha et al., 2007; Laursen et al., 2014; Walker et al., 2015) and population-based cohort studies (Osby et al., 2000a, 2000b; Miller et al., 2006; Laursen et al., 2007; Capasso et al., 2008; Piatt et al., 2010; Hoang et al., 2011; Partti and Perala, 2013; Nielsen et al., 2013; Lawrence et al., 2013; Sherman et al., 2013; Dickerson et al., 2014; Fazel et al., 2014; Olfson et al., 2015) have indicated that people with schizophrenia have excess mortality compared with general population or people without schizophrenia. With regard to the causes of death (CODs), people with schizophrenia have higher risk of dying from some unnatural CODs (suicide and violence) and some natural CODs (cardiovascular disease, diabetes mellitus, and smoking-related

⁎ Correspoding author at: Department of Public Health, College of Medicine, National Cheng Kung University, No. 1, Da Hsueh Road, Tainan 701, Taiwan. E-mail address: [email protected] (T.-H. Lu).

respiratory diseases). However, most of these cohort studies have small number of deaths and cannot further analyze the CODs by year and age. Another approach, although can explore only the tip of iceberg, is to use of multiple COD mortality file to examine the changes in ranking of leading CODs among decedents with mention of schizophrenia by year and age. The file include all diagnoses (up to a maximum of 20) reported on the death certificate of all U.S. decedent persons and standardize the assignment of underlying COD (National Center for Health Statistics, 2016). The multiple COD data can provide complement information in addition to underlying COD and could investigate the associations between diseases (Redelings et al., 2006; Redelings et al., 2007) and have been used in comparison of schizophrenia mortality between countries (Lu and Lin, 2010) and across years in the U.S. (Polednak, 2014), but not on the ranking of leading COD. This study sought to determine whether the ranking of leading CODs among U.S. decedents with mention of schizophrenia anywhere on the death certificate changed by age from 2000 to 2015 and differed from that among all decedents.

https://doi.org/10.1016/j.schres.2018.01.011 0920-9964/© 2018 Elsevier B.V. All rights reserved.

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J.-J. Lin et al. / Schizophrenia Research 197 (2018) 116–123

2. Methods 2.1. Data source The mortality multiple COD files are maintained by the National Center for Health Statistics for more than 40 years and are released yearly for research. The data of years 2000 through 2015 were used to identify decedent people aged 15 years old or above with mention of schizophrenia anywhere on the death certificates. 2.2. Measures The International Classification of Diseases, Tenth Revision (ICD-10) codes for leading CODs (simplified term used in Tables and Figure) were C00-C97 for malignant neoplasms (cancer); E10-E14 for diabetes mellitus (diabetes); F20 for schizophrenia; F01, F03, and G30 and for Alzheimer's disease and related dementia (ADRD); I00–I09, I11, I13, and I20–I51 for disease of heart (heart disease); I60–I69 for cerebrovascular diseases (stroke); J09-J18 for influenza and pneumonia

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(pneumonia); J40-J47 for chronic lower respiratory diseases (CLRD); K70, K73-K74 for chronic liver disease and cirrhosis (CLDC); V01-X59, Y85-Y86 for unintentional injuries (accidents); X60-X84, Y87.0 for intentional self-harm (suicide); X85-Y09, Y87.1 for assault (homicide) (Heron, 2016). 2.3. Analysis We calculated number and percentage of deaths of various leading CODs among people who died with mention of schizophrenia and among all decedents by age group (15–24, 25–44, 45–64, 65–74, and 75+ years old) and ranked the leading COD according to number of deaths. 3. Results The number of decedents aged 15 years old and above with mention of schizophrenia anywhere on the death certificates was 13,289, 13,655, 14,135, and 15,033 in 2000–2003, 2004–2007, 2008–2011 and

With mention of schizophrenia, 2000-2003

All decedents, 2000-2003



Fig. 1. Distribution of leading causes of death among all decedents aged 15 years old and above and decedents with mention of schizophrenia in the United States. (CLRD = Chronic lower respiratory disease; ADRD = Alzheimer's disease and related dementia).


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Fig. 1 (continued).

2012–2015, respectively. Fig. 1 presents the distribution of the leading CODs in each study period. Similar to all decedents, heart disease and cancer was the first and the second leading COD throughout the study years. Schizophrenia ranked the third in most years except in 2004–2007. ADRD was the 5th leading COD in 2008–2011 and the 4th in 2012–2015 (Table 1). Rankings of leading CODs by age are illustrated in Tables 2 to 6, respectively. For decedents aged 15–24 years old with mention of schizophrenia, suicide ranked the first leading COD throughout the study years. The percentage of suicide was 60% in 2000–203 and decreased to 46% in 2004–2007 and 47% in 2008–2011 and then increased to 57% in 2012–2015 (Table 2). The decedents with mention of schizophrenia in this age group had relative low percentage in dying from accidents (13% in 2012–2015) compared with all decedents aged 15–24 years old (41% in 2012–2015). For decedents aged 25–44 years old with mention of schizophrenia, the first leading COD was heart disease in 2000–2003, became suicide in 2004–2007 and 2008–2011, and then was accidents in 2012–2015

(Table 2). Suicide and accidents combined composed 26% of all deaths with mention of schizophrenia in 2000–2003 and increased to 30% in 2004–2007, 34% in 2008–2011, and 35% in 2002–2015. The percentage was similar to all decedents in this age group, which was 30% in 2000–2003, 34% in 2004–2007, 37% in 2008–2011, and 40% in 2012–2015. For decedents aged 45–64 years old with mention of schizophrenia, heart disease was the first leading COD followed by cancer throughout the study years. However, for all decedents in this age group, cancer ranked the first and followed by heart disease (Table 4). In 2012–2015, about one out of ten deaths was attributed to CLRD among decedents with mention of schizophrenia, but only 4% among all decedents in this age group. For decedents aged 65–74 years old with mention of schizophrenia, heart disease and cancer was the first and the second leading COD throughout the study years (Table 5). However, the first leading COD was cancer followed by heart disease among all decedents aged 65–74 years old. Heart disease and cancer combined accounted for



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Table 1 Leading Causes of Death (LCOD) Among All Decedents Aged 15 Years Old and Above and Decedents with Mention of Schizophrenia Anywhere on the Death Certificates in the United States, 2000 to 2015. 2000–2003

2004–2007

2008–2011

2012–2015

LCOD

N

%

LCOD

N

%

LCOD

N

%

LCOD

N

%

All decedents All causes Heart Dis Cancer Stroke CLRD Accidents Others

9,563,764 2,793,257 2,217,163 651,467 495,559 396,046 3,010,272

100.0 29.2 23.2 6.8 5.2 4.1 31.5

All causes Heart Dis Cancer Stroke ADRD CLRD Others

9,552,422 2,553,653 2,232,747 566,455 541,742 504,921 3,152,904

100.0 26.7 23.4 5.9 5.7 5.3 33.0

All causes Heart Dis Cancer ADRD CLRD Stroke Others

9,765,780 2,411,960 2,281,783 749,179 558,926 521,144 3,242,788

100.0 24.7 23.4 7.7 5.7 5.3 33.2

All causes Heart Dis Cancer ADRD CLRD Stroke Others

10,365,626 2,461,265 2,352,765 907,738 594,327 530,932 3,518,599

100.0 23.7 22.7 8.8 5.7 5.1 33.9

All causes Heart Dis Schizophrenia Cancer CLRD Diabetes Others

13,655 2887 1708 1697 1187 740 5436

100.0 21.1 12.5 12.4 8.7 5.4 39.8

All causes Heart Dis Cancer Schizophrenia CLRD ADRD Others

14,135 2755 1932 1401 1280 1142 5625

100.0 19.5 13.7 9.9 9.1 8.1 39.8

All causes Heart Dis Cancer Schizophrenia ADRD CLRD Others

15,033 2734 1926 1652 1341 1288 6092

100.0 18.2 12.8 11.0 8.9 8.6 40.5

Decedents with mention of schizophrenia All causes 13,289 100.0 Heart Dis 3007 22.6 Cancer 1632 12.3 Schizophrenia 1617 12.2 CLRD 1180 8.9 Stroke 685 5.2 Others 5168 38.9

Table 2 Leading Causes of Death (LCOD) Among All Decedents Aged 15–24 Years Old and Decedents with Mention of Schizophrenia Anywhere on the Death Certificates in the United States, 2000 to 2015. 2000–2003

2004–2007

2008–2011

2012–2015

LCOD

N

%

LCOD

N

%

LCOD

N

%

LCOD

N

%

All decedents All causes Accidents Assault Suicide Cancer Heart Dis Others

131,212 59,857 20,795 15,999 6869 4212 23,480

100.0 45.6 15.8 12.2 5.2 3.2 17.9

All causes Accidents Assault Suicide Cancer Heart Dis Others

137,526 63,976 21,895 16,888 6786 4345 23,636

100.0 46.5 15.9 12.3 4.9 3.2 17.2

All causes Accidents Assault Suicide Cancer Heart Dis Others

122,609 51,683 19,417 18,132 6567 4150 22,660

100.0 42.2 15.8 14.8 5.4 3.4 18.5

All causes Accidents Suicide Assault Cancer Heart Dis Others

117,703 48,293 20,352 17,856 6169 3860 21,173

100.0 41.0 17.3 15.2 5.2 3.3 18.0

All causes Suicide Accidents Heart Dis Schizophrenia Diabetes Others

101 46 15 6 6 3 25

100.0 45.5 14.9 5.9 5.9 3.0 24.8

All causes Suicide Accidents Schizophrenia Heart Dis Diabetes Others

98 46 17 7 6 2 20

100.0 46.9 17.3 7.1 6.1 2.0 20.4

All causes Suicide Accidents Schizophrenia Heart Dis CLRD Others

105 60 14 13 3 1 14

100.0 57.1 13.3 12.4 2.9 1.0 13.3

Decedents with mention of schizophrenia All causes 85 100.0 Suicide 51 60.0 Heart Dis 8 9.4 Accidents 8 9.4 Schizophrenia 5 5.9 Diabetes 2 2.4 Others 11 12.9


2004–2007

2008–2011

2012–2015

LCOD

N

%

LCOD

N

%

LCOD

N

%

LCOD

N

%

All decedents All causes Accidents Cancer Heart Dis Suicide HIV Dis Others

529,500 114,763 80,484 66,542 46,729 30,866 190,116

100.0 21.7 15.2 12.6 8.8 5.8 35.9

All causes Accidents Cancer Heart Dis Suicide Assault Others

504,006 126,126 71,094 62,938 46,979 31,107 165,762

100.0 25.0 14.1 12.5 9.3 6.2 32.9


464,154 120,963 63,244 56,796 49,146 28,067 145,938

100.0 26.1 13.6 12.2 10.6 6.0 31.4


473,976 134,470 59,739 55,137 53,179 28,470 142,981

100.0 28.4 12.6 11.6 11.2 6.0 30.2

All causes Suicide Heart Dis Accidents Schizophrenia Diabetes Others

1033 160 159 147 113 53 401

100.0 15.5 15.4 14.2 10.9 5.1 38.8

All causes Suicide Accidents Heart Dis Schizophrenia Diabetes Others

960 175 152 143 106 43 341

100.0 18.2 15.8 14.9 11.0 4.5 35.5

All causes Accidents Suicide Heart Dis Schizophrenia Diabetes Others

1005 186 169 159 110 47 334

100.0 18.5 16.8 15.8 10.9 4.7 33.2

Decedents with mention of schizophrenia All causes 1026 100.0 Heart Dis 155 15.1 Suicide 139 13.5 Accidents 126 12.3 Schizophrenia 108 10.5 Cancer 54 5.3 Others 444 43.3


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2004–2007

2008–2011

2012–2015

LCOD

N

%

LCOD

N

%

LCOD

N

%

LCOD

N

%

All decedents All causes Cancer Heart Dis Accidents Stroke Diabetes Others

1,682,379 566,265 403,568 89,402 63,785 61,029 498,330

100.0 33.7 24.0 5.3 3.8 3.6 29.6

All causes Cancer Heart Dis Accidents Diabetes Stroke Others

1,844,701 602,173 412,503 120,277 67,632 66,542 575,574

100.0 32.6 22.4 6.5 3.7 3.6 31.2

All causes Cancer Heart Dis Accidents CLRD CLDC Others

1,979,873 634,125 420,934 136,648 75,724 72,533 639,909

100.0 32.0 21.3 6.9 3.8 3.7 32.3

All causes Cancer Heart Dis Accidents CLDC CLRD Others

2,088,251 641,033 436,302 154,467 84,633 83,098 688,718

100.0 30.7 20.9 7.4 4.1 4.0 33.0

All causes Heart Dis Cancer CLRD Schizophrenia Diabetes Others

4685 1055 749 475 367 277 1762

100.0 22.5 16.0 10.1 7.8 5.9 37.6


5486 1164 944 549 399 333 2097

100.0 21.2 17.2 10.0 7.3 6.1 38.2


5831 1152 914 548 508 411 2298

100.0 19.8 15.7 9.4 8.7 7.0 39.4

Decedents with mention of schizophrenia All causes 3647 100.0 Heart Dis 822 22.5 Cancer 613 16.8 CLRD 393 10.8 Schizophrenia 287 7.9 Accidents 176 4.8 Others 1356 37.2

56% of deaths among all decedents in 2012–2015, but only 34% among decedents with mention schizophrenia. CLRD was the third leading COD in both groups. For decedents aged 75 years old and above with mention of schizophrenia, ADRD was the 4th leading COD in 2004–2007, became the 2nd in 2008–2011, and was the 1st in 2012–2015, a drastic increase in ranking during the study period (Table 6). However, for all decedents in this age group, ADRD ranked the 3rd from 2004 to 2007 to 2012–2015 followed by heart disease and cancer. The proportion of deaths for ADRD among decedents with mention of schizophrenia in 2012–2015 was 23%, which was higher than that among all decedents (15%). Fig. 2 summarizes the proportion of deaths for the first leading COD among all decedents and decedents with mention of schizophrenia by age in 2012–2015. The proportion of deaths for suicide (57%) among decedents with mention of schizophrenia aged 15–24 years old was disproportionally higher than the proportion for accidents among all decedents (41%) in the sage age group. 4. Discussion The findings of this study indicate that the first leading COD for decedents with mention of schizophrenia aged 15–24, 25–44, 45–64, 65–74, and 75+ years old in 2012–2015 was suicide, accidents, heart

disease, heart disease, and ADRD, respectively. Nevertheless, it was accidents, accidents, cancer, cancer, and heart disease, respectively for all decedents. A disproportionally higher percentage of dying from suicide among decedents with mention of schizophrenia aged 15–24 years old than all decedents in this age group (57% versus 17%) was noted. One possible explanation of higher proportion of suicide deaths among decedents with mention of schizophrenia, according to some suicide-related death certification studies (Roberts et al., 2000; Lindqvist and Gustafsson, 2002; Timmermans, 2005) was that medical certifiers (especially medical examiners or forensic pathologists) would more likely to record schizophrenia as a contributing COD on the death certificate if the patient with schizophrenia died from suicide than if the same patient died from natural CODs such as heart disease or cancer. In other words, decedents with mention of schizophrenia on the death certificates were the tips of iceberg of total patients with schizophrenia, in which certifiers judged that schizophrenia played a role contributing to death. In 2007, only 3355 decedents with mention of schizophrenia on the death certificates; however, it was estimated about 15,000 patients with schizophrenia died in 2007 according to the study of Olfson et al. (2015). Number of deaths for years 2001–2007 according to this study and Olfson et al.'s study and ratio between two studies are illustrated in Table 7. The ratio was around 0.15


2004–2007

2008–2011

2012–2015

LCOD

N

%

LCOD

N

%

LCOD

N

%

LCOD

N

%

All decedents All causes Cancer Heart Dis CLRD Stroke Diabetes Others

1,711,721 583,736 459,842 121,673 89,187 66,865 390,418

100.0 34.1 26.9 7.1 5.2 3.9 22.8

All causes Cancer Heart Dis CLRD Stroke Diabetes Others

1,580,680 554,542 380,427 115,273 75,183 62,969 392,286

100.0 35.1 24.1 7.3 4.8 4.0 24.8


1,628,079 573,947 360,063 127,573 71,020 61,067 434,409

100.0 35.3 22.1 7.8 4.4 3.8 26.7


1,857,307 630,927 402,020 142,569 77,587 71,757 532,447

100.0 34.0 21.6 7.7 4.2 3.9 28.7


2723 584 416 312 282 173 956

100.0 21.4 15.3 11.5 10.4 6.4 35.1

All causes Heart Dis Cancer CLRD Schizophrenia ADRD Others

3061 595 525 357 287 222 1075

100.0 19.4 17.2 11.7 9.4 7.3 35.1

All causes Heart Dis Cancer CLRD Schizophrenia ADRD Others

3831 704 611 443 437 278 1358

100.0 18.4 15.9 11.6 11.4 7.3 35.4

Decedents with mention of schizophrenia All causes 2932 100.0 Heart Dis 696 23.7 Cancer 458 15.6 CLRD 367 12.5 Schizophrenia 305 10.4 Stroke 160 5.5 Others 946 32.3



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Table 6 Leading Causes of Death (LCOD) Among All Decedents Aged 75 Years Old and Above and Decedents with Mention of Schizophrenia Anywhere on the Death Certificates in the United States, 2000 to 2015. 2000–2003

2004–2007

2008–2011

2012–2015

LCOD

N

%

LCOD

N

%

LCOD

N

%

LCOD

N

%

All decedents All causes Heart Dis Cancer Stroke ADRD CLRD Others

5,508,952 1,859,093 979,809 485,315 357,433 309,216 1,518,086

100.0 33.7 17.8 8.8 6.5 5.6 27.6

All causes Heart Dis Cancer ADRD Stroke CLRD Others

5,485,509 1,693,440 998,152 507,885 412,736 319,262 1,554,034

100.0 30.9 18.2 9.3 7.5 5.8 28.3


5,571,065 1,570,017 1,003,900 702,262 372,598 350,882 1,571,406

100.0 28.2 18.0 12.6 6.7 6.3 28.2


5,828,389 1,563,946 1,014,897 849,195 375,216 363,773 1,661,362

100.0 26.8 17.4 14.6 6.4 6.2 28.5

All causes Heart Dis Schizophrenia Cancer ADRD CLRD Others

5113 1083 940 486 405 370 1829

100.0 21.2 18.4 9.5 7.9 7.2 35.8

All causes Heart Dis ADRD Schizophrenia Cancer CLRD Others

4530 847 846 602 420 351 1464

100.0 18.7 18.7 13.3 9.3 7.7 32.3

All causes ADRD Heart Dis Schizophrenia Cancer CLRD Others

4261 972 716 584 364 274 1351

100.0 22.8 16.8 13.7 8.5 6.4 31.7

Decedents with mention of schizophrenia All causes 5599 100.0 Heart Dis 1326 23.7 Schizophrenia 912 16.3 Cancer 507 9.1 Stroke 407 7.3 CLRD 372 6.6 Others 2075 37.1

to 0.20 for most CODs and age groups. The ratio was relatively high for COPD (0.36) and suicide (0.31) among young adult people. The ratios (the shape of tip of iceberg) varied by causes of death and age groups, which indicate that people with schizophrenia listed on death certificates are likely to differ substantially from the broader population of individuals who died with schizophrenia. Young people with schizophrenia died from COPD or suicide, in which certifiers were more likely to record ‘schizophrenia’ on the death certificates. The statistics of leading COD is compiled based on the underlying COD, which is defined as the disease or injury that initiates the train of morbid events leading directly to death (World Health Organization, 2004). For example, one patient with schizophrenia had difficulty in swallowing, which is a common side effect of anti-psychotic medications which initiated train of morbid events (such as aspiration pneumonia and then sepsis) leading directly to death. In this circumstance, many certifiers would assign schizophrenia as the underlying COD. In

another scenario, the patient with schizophrenia was a heavy smoker for decades and has been diagnosed of having CLRD, which initiated train of morbid events (such as respiratory failure) leading directly to death. Most certifiers would assigned CLRD as the underlying COD and recorded schizophrenia as contributing COD on the death certificate. There is no one correct answer in assigning the underlying COD, it is based on the best judgement of the medical certifiers according to information available (Centers for Disease Control and Prevention, 2003). One of the strengths of this study is that it uses complete, nationwide, population-based data spanning 16 years. Another strength is the stratification of age of decedents into five groups (15–24, 25–44, 45–64, 65–74, and 75+ years old). The study of Olfson et al. (2015) confined to patients less than 65 years old and the study of Polednak (2014) stratified the age into two groups (15–64 and 65+ years old), which could not examine the changes in ranking of leading COD among older adult decedents with mention of schizophrenia. We noted a

Fig. 2. Proportion (%) of the first leading cause of death among all decedents and decedents with mention of schizophrenia by age in the United States, 2012–2015.


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Table 7 Number of deaths for years 2001–2007 according to Lin et al.'s (this) and Olfson et al.'s study and ratio between two studies by age and cause of death. Lin et al.'s (this) study Cause of death All causes Natural causes Cardiovascular Cancer Diabetes mellitus Renal failure Influenza or pneumonia Sepsis COPD Liver diseases Other natural causes Unnatural causes Suicide Accidents Assault (homicide) Undetermined intent

20–34 yr 697 322 79 12 27 2 11 3 5 4 179 375 232 104 13 26

35–54 yr 5225 4374 1318 607 264 30 97 41 323 124 1570 851 303 448 37 63

Olfson et al.'s study 55–64 yr 4631 4357 1321 843 256 58 92 46 558 49 1134 274 64 183 8 19

20–34 yr 4583 1896 547 107 132 14 52 28 14 32 970 2030 737 969 151 173

35–54 yr 35,815 25,222 8605 3831 1327 121 616 467 1370 889 7996 6236 1482 3713 361 680

Ratio (Lin/Olfson) 55–64 yr 33,605 28,623 10,229 5700 1510 192 934 759 2920 470 5909 1546 279 1071 70 126

20–34 yr 0.15 0.17 0.14 0.11 0.20 0.14 0.21 0.11 0.36 0.13 0.18 0.18 0.31 0.11 0.09 0.15

35–54 yr 0.15 0.17 0.15 0.16 0.20 0.25 0.16 0.09 0.24 0.14 0.20 0.14 0.20 0.12 0.10 0.09

55–64 yr 0.14 0.15 0.13 0.15 0.17 0.30 0.10 0.06 0.19 0.10 0.19 0.18 0.23 0.17 0.11 0.15

COPD = Chronic obstructive pulmonary disease.

drastic increase in the ranking and proportion of deaths attributed to ADRD among decedents aged 75 years old and above with mention of schizophrenia. Some limitations of this study should be noted. First, some medical certifiers might not correctly follow the guide in reporting CODs on the death certificates and resulted in under- or over-reporting of schizophrenia on the death certificates. As this study aims to examine the changes in the ranking of leading COD, it is unlikely that the behaviors of under- or over-reporting of schizophrenia on the death certificates by medical certifiers would skew to one side during the study period. Second, the underlying CODs might be incorrectly assigned because the medical certifiers recorded incorrect causal sequences in the part I of the death certificates (Lu et al., 2010; Cheng et al., 2012a, 2012b). Similarly, it is also unlikely the reporting behaviors would change during the past two decades as there were no interventions on death certification by the National Center for Health Statistics. Third, we could not obtain data on modifiable mortality risk factors such as lifestyle (smoking or physical activities), treatment (anti-psychotic drugs used) and process of delivery of care before death, which are relevant to interventions to reduce the preventable deaths. 5. Conclusion Despite these limitations, we can still conclude that the ranking of leading CODs among U.S. decedents with mention of schizophrenia changed across years and differed from all decedents by age, which suggest that different interventions should be designed accordingly. Conflict of interest The authors declare that we have no conflict of interest. Contributors Jin-Jia Lin, Fu-Weng Liang, Chung-Yi Li, and Tsung-Hsueh Lu all participated in the design, data analyses, and interpretation of the results. Jin-Jia Lin wrote the draft of the manuscript. All authors critical review the manuscript and have approved the final manuscript. Role of funding source This study was supported by the Chi-Mei & National Cheng Kung University Joint Program (CMNCKU10016). Funder has no role on the design of the study and interpretation of results. The contents are solely the responsibility of the authors. Acknowledgement We thank Bai-Hwang Lin for data analysis.

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