Research
`
`Original Investigation
`Premature Mortality Among Adults With Schizophrenia
`in the United States
`
`Mark Olfson, MD, MPH; Tobias Gerhard, PhD; Cecilia Huang, PhD; Stephen Crystal, PhD; T. Scott Stroup, MD, MPH
`
`IMPORTANCE Although adults with schizophrenia have a significantly increased risk of
`premature mortality, sample size limitations of previous research have hindered the
`identification of the underlying causes.
`
`OBJECTIVE To describe overall and cause-specific mortality rates and standardized mortality
`ratios (SMRs) for adults with schizophrenia compared with the US general population.
`
`DESIGN, SETTING, AND PARTICIPANTS We identified a national retrospective longitudinal
`cohort of patients with schizophrenia 20 to 64 years old in the Medicaid program (January 1,
`2001, to December 31, 2007). The cohort included 1 138 853 individuals, 4 807 121 years of
`follow-up, and 74 003 deaths, of which 65 553 had a known cause.
`
`MAIN OUTCOMES AND MEASURES Mortality ratios for the schizophrenia cohort standardized
`to the general population with respect to age, sex, race/ethnicity, and geographic region were
`estimated for all-cause and cause-specific mortality. Mortality rates per 100 000
`person-years and the mean years of potential life lost per death were also determined. Death
`record information was obtained from the National Death Index.
`
`RESULTS Adults with schizophrenia were more than 3.5 times (all-cause SMR, 3.7; 95% CI,
`3.7-3.7) as likely to die in the follow-up period as were adults in the general population.
`Cardiovascular disease had the highest mortality rate (403.2 per 100 000 person-years) and
`an SMR of 3.6 (95% CI, 3.5-3.6). Among 6 selected cancers, lung cancer had the highest
`mortality rate (74.8 per 100 000 person-years) and an SMR of 2.4 (95% CI, 2.4-2.5).
`Particularly elevated SMRs were observed for chronic obstructive pulmonary disease (9.9;
`95% CI, 9.6-10.2) and influenza and pneumonia (7.0; 95% CI, 6.7-7.4). Accidental deaths
`(119.7 per 100 000 person-years) accounted for more than twice as many deaths as suicide
`(52.0 per 100 000 person-years). Nonsuicidal substance-induced death, mostly from alcohol
`or other drugs, was also a leading cause of death (95.2 per 100 000 person-years).
`
`CONCLUSIONS AND RELEVANCE In a US national cohort of adults with schizophrenia, excess
`deaths from cardiovascular and respiratory diseases implicate modifiable cardiovascular risk
`factors, including especially tobacco use. Excess deaths directly attributable to alcohol or
`other drugs highlight threats posed by substance abuse. More aggressive identification and
`management of cardiovascular risk factors, as well as reducing tobacco use and substance
`abuse, should be leading priorities in the medical care of adults with schizophrenia.
`
`JAMA Psychiatry. 2015;72(12):1172-1181. doi:10.1001/jamapsychiatry.2015.1737
`Published online October 28, 2015.
`
`1172
`
`
`
`Copyright 2015 American Medical Association. All rights reserved.Copyright 2015 American Medical Association. All rights reserved.
`
`Editorial page 1166
`
`Supplemental content at
`jamapsychiatry.com
`
`Author Affiliations: Department of
`Psychiatry and New York State
`Psychiatric Institute, College of
`Physicians and Surgeons, Columbia
`University, New York (Olfson,
`Stroup); Center for Health Services
`Research on Pharmacotherapy,
`Chronic Disease Management, and
`Outcomes, Institute for Health,
`Health Care Policy and Aging
`Research, Rutgers, The State
`University of New Jersey, New
`Brunswick (Gerhard, Huang, Crystal);
`Department of Pharmacy Practice
`and Administration, Ernest Mario
`School of Pharmacy, Rutgers School
`of Health Related Professions,
`Piscataway, New Jersey (Gerhard).
`Corresponding Author: Mark Olfson,
`MD, MPH, Department of Psychiatry
`and New York State Psychiatric
`Institute, College of Physicians and
`Surgeons, Columbia University, 1051
`Riverside Dr, New York, NY 10032
`(mo49@cumc.columbia.edu).
`
`(Reprinted)
`
`jamapsychiatry.com
`
`Downloaded From: https://jamanetwork.com/ on 08/26/2020
`
`1
`
`Exhibit 2006
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`Causes of Premature Mortality Among US Adults With Schizophrenia
`
`Original Investigation Research
`
`A dults with schizophrenia are at markedly increased
`
`risk of premature death.1,2 Despite elevated rates of
`suicide and other unnatural causes of death, most of
`the excess mortality has been attributed to cardiovascular
`disease, respiratory disease, and other natural causes.3 One
`analysis from the United Kingdom found that suicide, homi-
`cide, and accidental deaths collectively accounted for 21 of
`164 schizophrenia deaths.4 Accurate characterizations of
`premature mortality patterns are important to inform clini-
`cal and policy initiatives to improve services and reduce
`preventable deaths in this patient population.
`Many factors, including economic disadvantage, nega-
`tive health behaviors, and difficulties accessing and adhering
`to medical treatments, are thought to contribute to pre-
`mature mortality in schizophrenia.5 Smoking,6 limited physi-
`cal activity,7 obesity,8 elevated serum glucose level,9
`hypertension,10 and dyslipidemia11 are all significantly more
`common in schizophrenia than in the general population.
`Adults with schizophrenia are also less likely than age-
`matched peers to receive adequate treatment for major medi-
`cal conditions,12 which may compound risk of premature
`mortality.13
`Research on early mortality in schizophrenia primarily
`derives from Western Europe.2 Because the United States
`differs from most Western European countries in its health
`and social welfare systems14 and in several relevant health
`indexes (including life expectancy,15 obesity,16 blood
`pressure,17 and tobacco use18), Western European mortality
`estimates for schizophrenia may not directly generalize to
`the United States.
`In the United States, premature mortality has been well
`documented in diagnostically mixed samples of patients
`with severe mental illness.19,20 Investigations in the United
`States limited to schizophrenia have primarily involved
`small samples (<1000 patients) published more than a quar-
`ter century ago.21,22 A recent US study23 comparing mortal-
`ity for schizophrenia research participants with a demo-
`graphically matched general population reference group
`reported a standardized mortality ratio (SMR) of 2.80, with
`all 25 deaths in the schizophrenia group occurring from
`natural causes. In a large cohort of US military veterans, it
`was further found that veterans with schizophrenia were
`significantly more likely than those without mental disor-
`ders to die of heart disease.24
`We conducted a national examination of premature
`mortality among adults with schizophrenia in the Medicaid
`program, the largest payer of health services for persons
`with schizophrenia in the United States.25 Mortality rates
`and mortality ratios standardized to the general population
`by age, sex, race/ethnicity, and geographic region were used
`to characterize the burden and excess mortality from sev-
`eral common medical diseases overall and stratified by
`demographic characteristics. By characterizing key sources
`of excess mortality in a large cohort with schizophrenia, the
`results provide a more comprehensive picture than was pre-
`viously available of the gap in mortality, highlighting the
`need for more effective strategies to improve the medical
`care of this patient population.
`
`Methods
`
`Sources of Data
`The total resident population and death information were ob-
`tainedfromtheJanuary1,2001,toDecember31,2007,USCom-
`pressed Mortality File.26 Age, sex, race/ethnicity, and year-
`specific life expectancy data were obtained from the 2006
`United States Life Tables.27 The schizophrenia cohort was ex-
`tractedfromthenationalMedicaidAnalyticeXtract(MAX)data
`from the Centers for Medicare & Medicaid Services.63 It in-
`cluded data from 45 states, not including Arizona, Delaware,
`Nevada, Oregon, and Rhode Island. Dates and cause of death
`information for the schizophrenia cohort were derived from
`linkage to the National Death Index (NDI), which provides a
`complete accounting of state-recorded deaths in the United
`States and is the most complete resource for tracing mortal-
`ityinnationalsamples.28Thedata,whicharedeidentified,were
`determined to be exempt from human participants review by
`the Rutgers University Institutional Review Board.
`
`Schizophrenia Cohort Assembly and Follow-up
`We identified a national retrospective longitudinal cohort of
`patients with schizophrenia 20 to 64 years old who received
`at least 2 outpatient claims or at least 1 inpatient claim for
`schizophrenia (ICD-10-CM code 295).29 The first observed day
`on which the inclusion criteria were met defined the start of
`follow-up. The cohort was followed forward until the loss of
`Medicaid eligibility, the date of death, or December 31, 2007
`(end of NDI-linked MAX data), whichever came first.
`
`Causes of Death
`All causes of death were first divided into natural and unnatu-
`ral causes. Natural causes were partitioned into cardiovascu-
`lar disease, cancer, diabetes mellitus, renal failure, influenza
`and pneumonia, sepsis, chronic obstructive pulmonary dis-
`ease (COPD), liver disease, and other natural causes. Cardio-
`vascular disease was subpartitioned into ischemic heart dis-
`ease, nonischemic heart disease, stroke, and other circulatory
`diseases. Cancer was subpartitioned into lung, colon, breast,
`liver, pancreas, hematologic, and other cancer. Unnatural
`causes were partitioned into suicide, accidents, assault (ho-
`micide), and injuries with undetermined intent and other in-
`juries (eTable 1 in the Supplement). In addition, an alterna-
`tive overlapping Centers for Disease Control and Prevention
`classification was used to define substance-induced deaths,
`including drug-induced and alcohol-induced deaths, and fire-
`arm-related deaths.30 Drug-induced nonsuicidal deaths were
`also partitioned into those induced by drugs of abuse (opi-
`oids, cannabinoids, sedatives or hypnotics, cocaine, stimu-
`lants, and volatile solvents) and others. Deaths related to le-
`gal interventions (eg, encounters with law enforcement
`officials) were also examined (eTable 2 in the Supplement).
`
`Sociodemographic Characteristics
`Based on Medicaid eligibility data, cohort members were
`classified by sex, age group (20-34, 35-44, 45-54, and 55-64
`years), and race/ethnicity (Hispanic, white non-Hispanic
`
`jamapsychiatry.com
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`(Reprinted) JAMA Psychiatry December 2015 Volume 72, Number 12
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`1173
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`Copyright 2015 American Medical Association. All rights reserved.Copyright 2015 American Medical Association. All rights reserved.
`
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`

`Research Original Investigation
`
`Causes of Premature Mortality Among US Adults With Schizophrenia
`
`[white], black non-Hispanic [black], and other non-Hispanic
`[other], including American Indian/Alaskan native, Asian,
`native Hawaiian/other Pacific Islander, and more than 1 race/
`ethnicity. Cohort members were also classified by geographic
`region (West, Midwest, South, and Northeast).
`
`Statistical Analysis
`In the schizophrenia cohort, person-years of follow-up, num-
`ber of deaths, and mortality rates per 100 000 person-years
`of follow-up were determined overall and stratified by demo-
`graphic characteristics. To facilitate comparisons of the mean
`years of lost life per death across causes of death, the mean
`years of potential lost life per death were calculated overall and
`for each cause of death as the mean of the remaining life ex-
`pectancyinyearsforeachdeceasedschizophreniacohortmem-
`ber at the age at death, as determined from the 2006 United
`States Life Tables based on the age at death, sex, and race/
`ethnicity.
`Cause-specificmortalityratesandSMRswith95%CIswere
`calculated for the entire schizophrenia cohort and stratified
`by age, sex, and race/ethnicity. Standardized mortality ratios
`are the ratio of the observed number of deaths in the schizo-
`phrenia cohort to the number of deaths expected in the same
`cohort based on data from the general US population (Janu-
`ary 1, 2001, to December 31, 2007, US Compressed Mortality
`File). A software program (SAS PROC STDRATE; SAS Institute
`Inc) was used to derive SMRs indirectly standardized by age,
`sex, race/ethnicity, and geographic region.
`
`Results
`All-Cause Mortality
`The schizophrenia cohort included 1 138 853 individuals,
`4 807 121 years of follow-up, and 74 003 deaths, of which
`65 553 had a known cause. The cohort sample sizes are strati-
`fied by state and payer type in eTable 3 in the Supplement, and
`the death counts are stratified by demographic group and spe-
`cific mortality in eTable 4 in the Supplement.
`The crude all-cause mortality rate for adults with schizo-
`phreniawashigherformenthanforwomenandincreasedwith
`age.Theratewashigherforpersonsofwhiterace/ethnicitythan
`for other racial/ethnic groups. These results are detailed in
`eTable 5 in the Supplement.
`Compared with the general population, the all-cause SMR
`for the schizophrenia cohort was significantly increased in the
`total sample and in each demographic group. The all-cause
`SMRs were higher for women than for men, for older adults
`than for younger or middle-aged adults, and for persons of
`white race/ethnicity than for the “other” racial/ethnic group,
`Hispanics, and blacks (Tables 1, 2, and 3). Standardized mor-
`tality ratios varied across the leading causes of death and age
`groups (Figure).
`
`Natural Causes of Death
`All Natural-Cause Mortality
`In the schizophrenia cohort, natural causes accounted for most
`of the known-cause deaths. Standardized mortality ratios from
`
`all natural causes of death were significantly elevated in the
`total schizophrenia cohort and in each demographic sub-
`group (Tables 1, 2, and 3).
`
`Cardiovascular Mortality
`Cardiovascular disease had the highest mortality rate of all dis-
`ease groups examined, accounting for approximately one-
`third of all natural deaths. Approximately one-half of cardio-
`vascular deaths were due to ischemic heart disease. The
`cardiovascular disease mortality rate was higher for men than
`for women, increased with age, and was highest for persons
`of white race/ethnicity and lowest for the “other” ethnic/
`racial group. Standardized mortality ratios for cardiovascular
`diseaseweresignificantlyelevatedineachdemographicgroup,
`particularly among women (4.6; 95% CI, 4.5-4.7), young adults
`(4.5; 95% CI, 4.1-4.8), and individuals of white race/ethnicity
`(4.9; 95% CI, 4.8-5.0) (Tables 1, 2, and 3).
`
`Cancer Mortality
`Canceraccountedforapproximately1in6naturaldeaths.Lung
`cancer had the highest mortality rate of the 6 selected spe-
`cificcancers.Thelungcancermortalityratewashigherformen
`than for women, for persons of white race/ethnicity than for
`otherracial/ethnicgroups,andforolderadultsthanformiddle-
`aged or younger adults.
`The SMR for cancer was significantly elevated in the total
`cohort but was only approximately half as large as the SMR for
`cardiovascular disease. The cancer SMR was significantly el-
`evated among all demographic groups except young adults
`(Tables 1, 2, and 3). The SMR for lung cancer was considerably
`larger than SMRs for the other specific cancers (Table 1).
`
`Other Natural Causes of Death
`Among the other specific natural causes of death, COPD, diabe-
`tesmellitus,andinfluenzaandpneumoniahadthehighestmor-
`tality rates (Table 1). For each of these diseases, SMRs were sig-
`nificantlyincreasedoverallandineachdemographicsubgroup.
`ParticularlyhighSMRswereevidentforCOPDandinfluenzaand
`pneumoniaexceptamongblackadultswithschizophrenia.The
`diabetes mellitus SMR was significantly higher among young
`adults than among middle-aged or older adults (Table 2).
`
`Unnatural Causes of Death
`Unnatural causes of death accounted for approximately 1 in 7
`known-cause deaths. Mortality due to unnatural causes was
`higherformenthanforwomenandformiddle-agedadultsthan
`for younger or older adults. Accidents followed a similar pat-
`tern. Among accidental deaths, poisoning and nonpoisoning
`accounted for similar numbers of deaths, although SMRs for
`poisoning were significantly larger than those for nonpoison-
`ing accidental deaths except among older adults.
`Suicide accounted for approximately one-quarter of un-
`natural deaths. Among all causes of death, suicide was asso-
`ciated with the highest mean years of potential life lost per
`death. Suicide mortality was higher in men than in women,
`decreased with age, and was highest for persons of white race/
`ethnicity.SuicideSMRsweresignificantlyelevatedinalldemo-
`graphic groups. The homicide SMR was not significantly in-
`
`1174
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`JAMA Psychiatry December 2015 Volume 72, Number 12 (Reprinted)
`
`jamapsychiatry.com
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`
`
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`Causes of Premature Mortality Among US Adults With Schizophrenia
`
`Original Investigation Research
`
`Table 1. Observed Deaths, Years of Potential Life Lost per Death, Mortality Rates, and Standardized Mortality Ratios of Adult Medicaid Beneficiaries
`Diagnosed as Having Schizophrenia by Disease Category and Sex (January 1, 2001, to December 31, 2007)a
`
`Total
`
`Observed
`Deaths
`74 003
`55 741
`19 381
`
`10 096
`
`5988
`
`1561
`
`1736
`
`9638
`3595
`679
`995
`315
`401
`648
`3005
`2969
`327
`1602
`
`1254
`4304
`1391
`14 875
`
`9812
`2498
`582
`5753
`2846
`2907
`979
`
`Potential
`Life Lost
`per Death,
`Mean, y
`28.5
`27.0
`26.8
`
`Mortality
`Rate
`1539.5
`1159.6
`403.2
`
`25.6
`
`28.9
`
`24.9
`
`25.8
`
`25.6
`24.6
`24.9
`27.5
`24.7
`24.5
`27.9
`26.1
`27.3
`26.0
`26.0
`
`25.7
`24.4
`29.0
`29.4
`
`35.7
`38.3
`35.6
`34.5
`36.8
`32.3
`36.1
`
`210.0
`
`124.6
`
`32.5
`
`36.1
`
`200.5
`74.8
`14.1
`20.7
`6.6
`8.3
`13.5
`62.5
`61.8
`6.8
`33.3
`
`26.1
`89.5
`28.9
`309.4
`
`204.1
`52.0
`12.1
`119.7
`59.2
`60.5
`20.4
`
`Cause of Death
`All causes
`Natural deaths
`Cardiovascular
`disease
`Ischemic heart
`disease
`Nonischemic
`heart disease
`Cerebrovas-
`cular disease
`Other
`circulatory
`disease
`Cancer
`Lung
`Colon
`Breast
`Liver
`Pancreas
`Hematologic
`Other cancer
`Diabetes mellitus
`Renal failure
`Influenza and
`pneumonia
`Sepsis
`COPD
`Liver disease
`Other natural
`deaths
`Unnatural deaths
`Suicide
`Homicide assault
`Accidents
`Poisoning
`Nonpoisoning
`Undetermined
`intent and other
`Abbreviations: COPD, chronic obstructive pulmonary disease;
`SMR, standardized mortality ratio (standardized for age, sex, race/ethnicity, and
`geographic region).
`a Schizophrenia mortality data are from the National Death Index of Medicaid
`beneficiaries. General population mortality data are from the Centers for
`
`Male
`
`Mortality
`Rate
`1576.3
`1152.1
`416.6
`
`228.9
`
`123.3
`
`29.5
`
`35.0
`
`185.3
`78.6
`13.1
`0.6
`8.9
`8.8
`14.4
`60.8
`52.8
`6.8
`34.2
`
`22.9
`83.8
`35.8
`313.8
`
`241.7
`63.7
`16.4
`140.0
`67.6
`72.4
`21.7
`
`SMR (95% CI)
`3.3 (3.3-3.3)
`3.0 (3.0-3.0)
`3.1 (3.0-3.1)
`
`3.1 (3.0-3.2)
`
`3.4 (3.3-3.5)
`
`2.0 (1.8-2.1)
`
`3.3 (3.1-3.5)
`
`1.7 (1.7-1.8)
`2.4 (2.3-2.5)
`1.6 (1.4-1.8)
`3.6 (1.8-5.4)
`1.3 (1.1-1.5)
`1.3 (1.2-1.5)
`1.4 (1.3-1.6)
`1.4 (1.3-1.7)
`3.4 (3.2-3.6)
`3.5 (3.0-4.0)
`6.5 (6.1-7.0)
`
`4.1 (3.8-4.5)
`9.9 (9.5-10.3)
`1.9 (1.8-2.0)
`3.8 (3.7-3.9)
`
`5.0 (4.8-5.2)
`3.2 (3.0-3.3)
`0.9 (0.8-1.0)
`2.6 (2.5-2.7)
`4.1 (3.9-4.3)
`2.0 (1.9-2.1)
`5.0 (4.6-5.4)
`
`Female
`
`Mortality
`Rate
`1497.0
`1168.2
`387.7
`
`188.4
`
`126.0
`
`35.9
`
`37.4
`
`217.9
`70.4
`15.3
`43.8
`3.8
`7.8
`12.4
`64.5
`72.1
`6.8
`32.4
`
`29.7
`96.2
`21.0
`304.4
`
`160.9
`38.5
`7.2
`96.3
`49.5
`46.8
`18.8
`
`SMR (95% CI)
`4.3 (4.3-4.4)
`3.7 (3.7-3.8)
`4.6 (4.5-4.7)
`
`5.2 (5.0-5.4)
`
`4.8 (4.6-5.0)
`
`2.5 (2.3-2.6)
`
`4.6 (4.3-4.9)
`
`1.8 (1.8-1.8)
`2.5 (2.4-2.6)
`1.9 (1.7-2.1)
`1.6 (1.5-1.7)
`1.5 (1.2-1.9)
`1.4 (1.2-1.6)
`1.5 (1.3-1.7)
`1.6 (1.5-1.7)
`5.2 (4.9-5.4)
`3.8 (3.2-4.4)
`7.8 (7.2-8.4)
`
`5.0 (4.6-5.4)
`10.0 (9.6-10.4)
`2.1 (1.9-2.3)
`4.8 (4.7-5.0)
`
`2.5 (2.5-2.6)
`6.9 (6.5-7.4)
`1.9 (1.6-2.2)
`4.7 (4.5-4.9)
`6.5 (6.1-6.9)
`3.6 (3.4-3.9)
`7.8 (7.1-8.6)
`
`SMR (95% CI)
`3.7 (3.7-3.7)
`3.3 (3.3-3.3)
`3.6 (3.5-3.6)
`
`3.7 (3.6-3.8)
`
`3.9 (3.8-4.0)
`
`2.2 (2.1-2.3)
`
`3.8 (3.7-4.0)
`
`1.8 (1.7-1.8)
`2.4 (2.4-2.5)
`1.7 (1.6-1.8)
`1.6 (1.5-1.7)
`1.4 (1.2-1.5)
`1.4 (1.2-1.5)
`1.4 (1.3-1.6)
`1.5 (1.4-1.5)
`4.2 (4.0-4.3)
`3.6 (3.2-4.0)
`7.0 (6.7-7.4)
`
`4.6 (4.3-4.8)
`9.9 (9.6-10.2)
`2.0 (1.9-2.1)
`4.2 (4.1-4.3)
`
`3.1 (3.0-3.2)
`3.9 (3.8-4.1)
`1.1 (1.0-1.2)
`3.2 (3.1-3.2)
`4.8 (4.6-4.9)
`2.4 (2.3-2.4)
`5.9 (5.5-6.3)
`
`Disease Control and Prevention WONDER data.64 Mortality rates are
`expressed per 100 000 person-years. The deaths of 8450 individuals were
`classified as unknown, undetermined, or unspecified. Male and female SMRs
`are standardized for age, race/ethnicity, and geographic region.
`
`creased in the total schizophrenia cohort, although it was
`significantly increased among women, middle-aged and older
`adults, and persons of white race/ethnicity (Tables 1, 2, and 3).
`
`Deaths From Substances, Firearms, and Legal Intervention
`Under the alternative Centers for Disease Control and Preven-
`tion classification, substance-induced deaths accounted for
`8.2% of known-cause deaths and were most commonly non-
`suicidedeaths.Alcohol-inducedanddrug-induceddeathsfrom
`drugs of abuse collectively accounted for most substance-
`
`induced deaths that were not classified as suicides. Standard-
`ized mortality ratios were significantly elevated for substance-
`induced suicide and nonsuicide deaths, firearm deaths, and
`deaths due to legal interventions (Table 4).
`
`Discussion
`Nonelderly adults with schizophrenia in the Medicaid pro-
`gram die at approximately 3.5 times the rate of the general
`
`jamapsychiatry.com
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`(Reprinted) JAMA Psychiatry December 2015 Volume 72, Number 12
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`1175
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`
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`

`Research Original Investigation
`
`Causes of Premature Mortality Among US Adults With Schizophrenia
`
`Table 2. Mortality Rates and Standardized Mortality Ratios of Adult Medicaid Beneficiaries Diagnosed as Having Schizophrenia by Disease Category
`and Age Group (January 1, 2001, to December 31, 2007)a
`
`20-34 y
`Mortality Rate
`459.6
`190.1
`54.9
`14.8
`
`32.0
`
`3.0
`
`5.0
`
`10.7
`0.5
`0.8
`0.8
`0.2
`0.2
`3.3
`4.9
`13.2
`1.4
`5.2
`
`2.8
`1.4
`3.2
`97.3
`203.6
`73.9
`15.1
`97.2
`55.0
`42.2
`17.4
`
`SMR (95% CI)
`3.6 (3.5-3.7)
`3.8 (3.6-4.0)
`4.5 (4.1-4.8)
`5.2 (4.4-6.0)
`
`4.7 (4.2-5.2)
`
`2.2 (1.4-2.9)
`
`3.9 (2.8-5.0)
`
`1.2 (1.0-1.4)
`1.4 (0.2-2.7)
`1.5 (0.5-2.6)
`1.0 (0.3-1.8)
`0.7 (0.0-1.6)
`1.6 (0.0-3.7)
`1.4 (1.0-1.9)
`1.1 (0.8-1.4)
`7.3 (6.0-8.5)
`6.2 (3.0-9.5)
`5.6 (4.1-7.1)
`
`3.2 (2.0-4.4)
`9.7 (4.6-14.8)
`2.8 (1.8-3.8)
`4.1 (3.9-4.4)
`2.6 (2.5-2.8)
`5.3 (4.9-5.7)
`0.7 (0.6-0.8)
`2.6 (2.4-2.8)
`5.7 (5.2-6.2)
`1.5 (1.4-1.7)
`6.4 (5.5-7.4)
`
`Cause of Death
`All causes
`Natural deaths
`Cardiovascular disease
`Ischemic heart
`disease
`Nonischemic heart
`disease
`Cerebrovascular
`disease
`Other circulatory
`disease
`Cancer
`Lung
`Colon
`Breast
`Liver
`Pancreas
`Hematologic
`Other cancer
`Diabetes mellitus
`Renal failure
`Influenza and
`pneumonia
`Sepsis
`COPD
`Liver disease
`Other natural deaths
`Unnatural deaths
`Suicide
`Homicide assault
`Accidents
`Poisoning
`Nonpoisoning
`Undetermined intent
`and other
`Abbreviations: COPD, chronic obstructive pulmonary disease;
`SMR, standardized mortality ratio (standardized for age, sex, race/ethnicity, and
`geographic region).
`a Schizophrenia mortality data are from the National Death Index of Medicaid
`
`35-54 y
`Mortality Rate
`1233.5
`868.7
`296.4
`142.5
`
`111.2
`
`18.5
`
`24.1
`
`131.9
`45.5
`8.6
`14.4
`4.7
`5.3
`10.1
`43.4
`45.7
`4.2
`21.2
`
`16.1
`47.2
`30.6
`275.4
`214.8
`51.0
`12.4
`127.9
`71.3
`56.6
`23.4
`
`SMR (95% CI)
`3.4 (3.4-3.5)
`3.0 (3.0-3.0)
`3.2 (3.1-3.3)
`3.3 (3.2-3.4)
`
`3.9 (3.7-4.0)
`
`1.5 (1.4-1.6)
`
`3.2 (2.9-3.4)
`
`1.6 (1.5-1.6)
`2.4 (2.2-2.5)
`1.4 (1.2-1.6)
`1.3 (1.2-1.4)
`1.1 (1.0-1.3)
`1.2 (1.0-1.4)
`1.5 (1.3-1.6)
`1.4 (1.3-1.4)
`4.1 (3.9-4.3)
`3.0 (2.4-3.5)
`5.2 (4.8-5.6)
`
`3.5 (3.2-3.8)
`11.0 (10.4-11.6)
`2.0 (1.8-2.1)
`3.7 (3.6-3.8)
`3.2 (3.1-3.3)
`3.7 (3.5-3.8)
`1.3 (1.2-1.5)
`3.2 (3.1-3.3)
`4.6 (4.4-4.8)
`2.3 (2.2-2.4)
`6.0 (5.5-6.4)
`
`55-64 y
`Mortality Rate
`3707.2
`3157.6
`1128.4
`640.9
`
`269.2
`
`109.7
`
`108.7
`
`628.8
`250.3
`46.6
`62.9
`19.5
`27.1
`35.4
`187.0
`166.6
`21.2
`103.0
`
`83.7
`322.1
`51.9
`651.9
`170.6
`30.8
`7.7
`118.2
`25.3
`92.9
`13.9
`
`SMR (95% CI)
`4.0 (4.0-4.1)
`3.6 (3.6-3.7)
`4.0 (3.9-4.0)
`4.1 (4.0-4.2)
`
`4.0 (3.8-4.1)
`
`3.0 (2.8-3.2)
`
`4.5 (4.3-4.8)
`
`1.9 (1.9-2.0)
`2.5 (2.4-2.6)
`2.0 (1.8-2.2)
`1.9 (1.7-2.1)
`1.6 (1.4-1.8)
`1.4 (1.2-1.6)
`1.4 (1.3-1.6)
`1.6 (1.5-1.7)
`4.1 (3.9-4.3)
`4.1 (3.5-4.7)
`9.4 (8.8-10.0)
`
`5.8 (5.4-6.2)
`9.5 (9.2-9.9)
`1.9 (1.8-2.1)
`5.1 (5.0-5.2)
`3.5 (3.3-3.7)
`2.9 (2.6-3.3)
`2.1 (1.6-2.6)
`3.8 (3.5-4.0)
`4.1 (3.5-4.6)
`3.7 (3.4-3.9)
`5.0 (4.2-5.9)
`
`beneficiaries. General population mortality data are from the Centers for
`Disease Control and Prevention WONDER data.64 Mortality rates are
`expressed per 100 000 person-years. The deaths of 8450 individuals were
`classified as unknown, undetermined, or unspecified.
`
`population. Their increased risk of mortality was distributed
`across several diseases but was particularly elevated for COPD,
`influenza and pneumonia, diabetes mellitus, cardiovascular
`disease, and suicide. In absolute terms, the leading identified
`causes of death were cardiovascular disease, cancer, and ac-
`cidents. These patterns have implications for the medical care
`of patients with schizophrenia.
`The 3.7 SMR for all-cause mortality was higher than the
`corresponding2.98SMRfromameta-analysisof38studiesthat
`collectively included 22 296 deaths.3 Our higher figure is con-
`sistent with a trend in the meta-analysis toward an increas-
`ing all-cause SMR in recent decades (the statistical test in the
`meta-analysis was significant at P = .03).3 A French study31 of
`3470 patients with schizophrenia aged 18 to 64 years old, con-
`
`ducted between 1993 and 2005, reported all-cause SMRs of 3.6
`for men and 4.3 for women, resembling the present findings.
`Increased relative risk of cardiovascular mortality was ob-
`served for 3 age groups (20-34, 35-54, and 55-64), both sexes,
`and all 4 racial/ethnic groups. The number of age groups was
`reduced in the cause of death analysis to simplify the data pre-
`sentation. Previous schizophrenia studies have reported sig-
`nificant, although smaller, increases in the relative risk for car-
`diovascular mortality for men,32 women,33 and younger
`adults.34 Incomplete follow-up, sampling from hospital dis-
`charges, and short follow-up periods may have depressed prior
`estimates. The relative risk of cardiovascular mortality was
`lower among black adults than among white or Hispanic adults
`in part because of the higher background cardiovascular mor-
`
`1176
`
`JAMA Psychiatry December 2015 Volume 72, Number 12 (Reprinted)
`
`jamapsychiatry.com
`
`
`
`Copyright 2015 American Medical Association. All rights reserved.Copyright 2015 American Medical Association. All rights reserved.
`
`Downloaded From: https://jamanetwork.com/ on 08/26/2020
`
`5
`
`

`

`Cause of Death
`All causes
`Natural deaths
`Cardiovascular
`disease
`Ischemic
`heart disease
`Nonischemic
`heart disease
`Cerebrovas-
`cular disease
`Other
`circulatory
`disease
`Cancer
`Lung
`Colon
`Breast
`Liver
`Pancreas
`Hematologic
`Other cancer
`Diabetes
`mellitus
`Renal failure
`Influenza and
`pneumonia
`Sepsis
`COPD
`Liver disease
`Other natural
`deaths
`Unnatural deaths
`Suicide
`Homicide
`assault
`Accidents
`Poisoning
`Nonpoisoning
`Undetermined
`intent and other
`Abbreviations: COPD, chronic obstructive pulmonary disease;
`SMR, standardized mortality ratio (standardized for age, sex, race/ethnicity, and
`geographic region).
`a Schizophrenia mortality data are from the National Death Index of Medicaid
`beneficiaries. General population mortality data are from the Centers for
`Disease Control and Prevention WONDER data.64 Mortality rates are
`
`251.3
`
`134.2
`
`33.3
`
`37.3
`
`235.3
`93.8
`16.4
`20.1
`6.6
`9.7
`15.9
`72.8
`61.5
`
`7.5
`43.0
`
`29.3
`133.0
`33.1
`348.4
`
`260.0
`71.9
`8.7
`
`152.1
`78.9
`73.2
`27.2
`
`4.6 (4.5-4.7)
`
`6.0 (5.8-6.2)
`
`3.6 (3.3-3.8)
`
`5.7 (5.4-6.1)
`
`2.0 (2.0-2.1)
`2.8 (2.7-2.9)
`2.2 (2.0-2.4)
`1.7 (1.5-1.8)
`2.0 (1.7-2.3)
`1.5 (1.4-1.7)
`1.7 (1.5-1.8)
`1.7 (1.6-1.7)
`5.6 (5.3-5.9)
`
`6.0 (5.2-6.9)
`10.8 (10.1-11.4)
`
`7.2 (6.7-7.7)
`11.4 (10.9-11.7)
`2.2 (2.0-2.4)
`6.3 (6.2-6.4)
`
`3.9 (3.8-4.0)
`3.9 (3.7-4.1)
`2.3 (2.0-2.7)
`
`3.8 (3.7-3.9)
`5.8 (5.5-6.0)
`2.8 (2.6-2.9)
`7.7 (7.1-8.3)
`
`172.3
`
`135.7
`
`37.9
`
`43.8
`
`176.4
`57.9
`13.3
`24.6
`5.9
`8.3
`10.4
`56.0
`72.1
`
`8.3
`24.2
`
`27.0
`39.9
`21.1
`309.1
`
`132.5
`22.5
`19.9
`
`77.6
`31.1
`46.5
`12.5
`
`2.2 (2.1-2.2)
`
`2.2 (2.1-2.3)
`
`1.4 (1.3-1.5)
`
`2.4 (2.2-2.6)
`
`1.2 (1.2-1.3)
`1.5 (1.4-1.6)
`1.1 (1.0-1.3)
`1.3 (1.2-1.5)
`0.9 (0.7-1.1)
`1.1 (0.9-1.3)
`0.9 (0.8-1.1)
`1.1 (1.0-1.2)
`2.8 (2.6-3.0)
`
`2.2 (1.8-2.6)
`3.2 (2.9-3.6)
`
`2.5 (2.2-2.8)
`4.7 (4.3-5.1)
`1.3 (1.1-1.4)
`2.3 (2.3-2.4)
`
`1.5 (1.5-1.6)
`2.9 (2.6-3.2)
`0.7 (0.6-0.8)
`
`1.7 (1.6-1.8)
`2.0 (1.8-2.2)
`1.6 (1.4-1.7)
`2.7 (2.3-3.1)
`
`Causes of Premature Mortality Among US Adults With Schizophrenia
`
`Original Investigation Research
`
`Table 3. Mortality Rates and Standardized Mortality Ratios of Adult Medicaid Beneficiaries Diagnosed as Having Schizophrenia by Disease Category
`and Racial/Ethnic Group (January 1, 2001, to December 31, 2007)a
`
`White Non-Hispanic
`Mortality
`Rate
`1769.9
`1346.9
`456.0
`
`SMR (95% CI)
`4.7 (4.6-4.7)
`4.3 (4.3-4.4)
`4.9 (4.8-5.0)
`
`Black Non-Hispanic
`Mortality
`Rate
`1402.3
`1067.8
`389.6
`
`SMR (95% CI)
`3.2 (3.2-3.3)
`2.0 (2.0-2.0)
`2.1 (2.0-2.1)
`
`Other Non-Hispanicb
`Mortality
`Rate
`754.5
`484.7
`172.7
`
`SMR (95% CI)
`3.9 (3.7-4.1)
`3.1 (2.9-3.3)
`3.6 (3.2-4.0)
`
`Hispanic
`Mortality
`Rate
`1016.9
`678.8
`220.2
`
`SMR (95% CI)
`3.8 (3.7-4.0)
`3.1 (3.0-3.3)
`3.6 (3.3-3.9)
`
`93.9
`
`51.3
`
`13.5
`
`14.0
`
`86.4
`25.4
`5.9
`13.5
`5.9
`2.2
`5.4
`28.1
`38.3
`
`0.5
`11.9
`
`12.4
`16.2
`20.5
`125.8
`
`137.1
`45.9
`6.5
`
`68.6
`31.3
`37.3
`16.2
`
`4.1 (3.5-4.7)
`
`113.0
`
`3.6 (3.2-4.0)
`
`4.6 (3.7-5.6)
`
`1.4 (0.8-1.9)
`
`3.5 (2.2-5.0)
`
`1.4 (1.2-1.7)
`2.2 (1.6-2.8)
`1.3 (0.5-2.1)
`2.0 (1.2-2.7)
`1.0 (0.4-1.6)
`0.7 (0.0-1.3)
`1.1 (0.4-1.8)
`1.2 (0.9-1.6)
`5.4 (4.1-6.6)
`
`1.0 (0.0-3.0)
`5.8 (3.4-8.2)
`
`6.7 (4.0-9.5)
`7.8 (5.0-10.6)
`2.2 (1.5-2.9)
`4.5 (4.0-5.1)
`
`3.7 (3.3-4.2)
`4.9 (3.8-5.9)
`1.4 (0.6-2.2)
`
`3.2 (2.7-3.8)
`7.8 (5.8-9.8)
`2.2 (1.7-2.7)
`10.8 (6.9-14.6)
`
`66.0
`
`19.5
`
`21.8
`
`98.5
`22.1
`8.0
`12.2
`7.3
`5.0
`11.1
`32.8
`47.3
`
`4.2
`19.5
`
`11.1
`27.9
`40.5
`209.9
`
`157.2
`33.6
`11.5
`
`102.6
`58.0
`44.6
`9.5
`
`4.6 (3.9-5.3)
`
`1.9 (1.4-2.5)
`
`4.4 (3.2-5.5)
`
`1.6 (1.4-1.7)
`2.4 (1.8-3.0)
`1.6 (0.9-2.4)
`1.6 (1.1-2.2)
`1.5 (0.8-2.2)
`1.4 (0.6-2.1)
`1.6 (1.0-2.1)
`1.3 (1.0-1.5)
`4.0 (3.3-4.7)
`
`4.4 (1.8-7.0)
`5.7 (4.1-7.3)
`
`3.3 (2.1-4.5)
`11.6 (9.0-14.3)
`2.4 (2.0-2.9)
`3.8 (3.5-4.2)
`
`3.3 (3.0-3.6)
`5.0 (3.9-6.0)
`1.3 (0.8-1.8)
`
`3.4 (3.0-3.8)
`6.3 (5.3-7.3)
`2.1 (1.7-2.5)
`4.8 (2.9-6.7)
`
`expressed per 100 000 person-years. The deaths of 8450 individuals were
`classified as unknown, undetermined, or unspecified.
`b Excludes 105 277 individuals with missing race/ethnicity. Other non-Hispanic
`includes 8759 American Indians, 13 717 Asian/Pacific Islanders, 18 419 native
`Hawaiians, and 833 individuals with 2 or more races/ethnicities.
`
`tality in the general black population.35 Excess cardiovascu-
`lar mortality was evident even in young adults. These pat-
`terns highlight the importance of an early clinical focus on
`cardiovascularhealthinthemanagementofschizophrenia.Ad-
`dressing the disparity in cardiovascular death will likely re-
`quire increased focus on primary prevention and on the iden-
`tification and management of conditions contributing to
`cardiovascular mortality risk, including diabetes mellitus, hy-
`pertension, hyperlipidemia, and coronary artery disease. Be-
`cause some antipsychotic medications are known to increase
`
`risk for cardiovascular disease and have been associated with
`increased risk of sudden cardiac death, myocarditis, and
`cardiomyopathy,36 long-term studies are needed to deter-
`mine whether and to what extent antipsychotic treatment con-
`tributes to cardiovascular mortality in schizophrenia.
`High mortality rates and SMRs were also observed for
`COPD, lung cancer, and influenza and pneumonia. Together
`withelevatedcardiovasculardeathrisk,thesepatternsstrongly
`implicate smoking as a major risk factor for premature mor-
`talityinschizophreniaintheUnitedStates.Approximatelytwo-
`
`jamapsychiatry.com
`
`(Reprinted) JAMA Psychiatry December 2015 Volume 72, Number 12
`
`1177
`
`
`
`Copyright 2015 American Medical Association. All rights reserved.Copyright 2015 American Medical Association. All rights reserved.
`
`Downloaded From: https://jamanetwork.com/ on 08/26/2020
`
`6
`
`

`

`Research Original Investigation
`
`Causes of Premature Mortality Among US Adults With Schizophrenia
`
`Figure. Standardized Mortality Ratios of Adult Medicaid Beneficiaries
`Diagnosed as Having Schizophrenia for 10 Common Causes of Death
`by Age Group (January 1, 2001, to December 31, 2007)
`
`Cause of Death
`
`COPD
`(n = 4304)
`
`Influenza and pneumonia
`(n = 1602)
`
`Diabetes mellitus
`(n = 2969)
`
`Suicide
`(n = 2498)
`
`Ischemic heart disease
`(n = 10 096)
`
`Nonischemic heart disease
`(n = 5988)
`
`Accidents
`(n = 5753)
`
` Cerebrovascular disease
`(n = 1561)
`
`Liver disease
`(n = 1391)
`
`Lung cancer
`(n = 3595)
`
`20-34 y
`35-54 y
`55-64 y
`
`0
`
`2
`
`4
`
`6
`SMR
`
`8
`
`10
`
`12
`
`Schizophrenia mortality data are from the Nat