Context
Despite improvements in mental health services in recent decades, it is unclear whether the risk of mortality in schizophrenia has changed over time.
Objective
To explore the distribution of standardized mortality ratios (SMRs) for people with schizophrenia.
Data Sources
Broad search terms were used in MEDLINE, PsychINFO, Web of Science, and Google Scholar to identify all studies that investigated mortality in schizophrenia, published between January 1, 1980, and January 31, 2006. References were also identified from review articles, reference lists, and communication with authors.
Study Selection
Population-based studies that reported primary data on deaths in people with schizophrenia.
Data Extraction
Operationalized criteria were used to extract key study features and mortality data.
Data Synthesis
We examined the distribution of SMRs and pooled selected estimates using random-effects meta-analysis. We identified 37 articles drawn from 25 different nations. The median SMR for all persons for all-cause mortality was 2.58 (10%-90% quantile, 1.18-5.76), with a corresponding random-effects pooled SMR of 2.50 (95% confidence interval, 2.18-2.43). No sex difference was detected. Suicide was associated with the highest SMR (12.86); however, most of the major causes-of-death categories were found to be elevated in people with schizophrenia. The SMRs for all-cause mortality have increased during recent decades (P = .03).
Conclusions
With respect to mortality, a substantial gap exists between the health of people with schizophrenia and the general community. This differential mortality gap has worsened in recent decades. In light of the potential for second-generation antipsychotic medications to further adversely influence mortality rates in the decades to come, optimizing the general health of people with schizophrenia warrants urgent attention.
It is now widely acknowledged that schizophrenia contributes substantially to the global burden of disease.1,2 It is also well known that schizophrenia is associated with elevated suicide rates.3 Less widely appreciated is the fact that people with schizophrenia are at increased risk for premature death associated with comorbid somatic conditions.4 Apart from adverse effects related to medication, schizophrenia can trigger a cascade of socioeconomic and lifestyle factors that, in turn, can translate into adverse physical health outcomes. These comorbid physical conditions contribute to increased mortality risks among people with schizophrenia.
The association between severe mental illness and increased mortality rates has long been recognized.5 With respect to the group of disorders now labeled schizophrenia, increased mortality rates have been the object of scrutiny since the early 20th century.6-8 The quality of research on this topic has improved greatly in recent decades, with access to larger, better-characterized samples and the availability of high-quality mortality data for the general population. Access to these data allows the calculation of the standardized mortality ratio (SMR), which compares mortality in people with schizophrenia vs the general population. The SMRs are calculated by dividing the observed mortality rates in a given population (eg, the number of deaths in a group of individuals with schizophrenia) by the expected mortality rates in that same group as predicted by age- and sex-specific mortality rates for a standard population. Thus, an SMR of 2.0 would indicate that people with schizophrenia are twice as likely to die compared with the general population. The SMRs can be calculated for overall mortality (all-cause) or for more specific, widely used categories (eg, cancer, cardiovascular disease, endocrine disorders, or suicide).
In recent years, several scholarly reviews4,9-11 have noted higher mortality in schizophrenia compared with the general population. A meta-analysis,4 based on 18 studies published between 1969 and 1996, reported an all-cause SMR for people with schizophrenia of 1.51. Another meta-analysis,11 based on 20 studies published between 1973 and 1995, reported a similar SMR for people with schizophrenia (1.57). Although these 2 systematic reviews agreed on the size of the pooled SMR associated with schizophrenia, there were discrepancies in the sex difference of overall mortality ratios. Brown4 found a small but significant male excess in the overall mortality ratio, whereas other studies12,13 reported either no sex difference11 or higher mortality ratios in females compared with males.
In collating data from different sites, systematic reviewers need to appreciate the structure of the underlying data. In light of the differing population age structure and disease profile among sites,1,14 we would expect substantial variation in mortality ratios among sites. For example, one would predict that SMRs for people with schizophrenia would differ between developed and developing nations, where the profiles of disease and the access to services vary markedly.
Because of the increased focus on mental health care seen in many countries during the last few decades, one might predict that SMRs associated with disorders such as schizophrenia should be decreasing over time.15,16 However, several authors have suggested that SMRs in schizophrenia have been increasing during recent decades. For example, Osby et al17 found a linear increasing trend of mortality during 5-year periods from 1976 to 1995 among people with schizophrenia. The meta-analysis by Brown4 also reported significantly higher mortality in the 1980s compared with the 1970s. Deinstitutionalization may have influenced recent secular changes in mortality rates in schizophrenia. Although deinstitutionalization started in the 1950s, findings on its relationship to mortality have been inconsistent.10,11,18
The aims of this study were to undertake a systematic review of mortality in schizophrenia and to examine a limited number of planned sensitivity analyses. In keeping with our previous systematic review of the incidence19 and prevalence20 of schizophrenia and considering that variability is to be expected in systematic reviews of SMRs,4,21 we sought to preserve the expected variation in the data rather than to focus only on pooled values derived from meta-analysis. Thus, for the main analyses, we present distributions of mortality estimates with measures of central tendency (eg, median or means) and quantiles (10% and 90% quantiles). On the basis of all-cause SMR, we predicted that the SMRs of males and females would not differ significantly. We also predicted that SMRs from the developed world would differ from those from the developing world (nondirectional hypothesis). We wished to explore the impact of study quality on SMRs. With the assumption that higher-quality studies would be more likely to identify deaths in schizophrenia, we predicted that SMRs derived from such studies would be higher compared with those from lower-quality studies. On the basis of previous systematic reviews and commentaries, we predicted that SMRs would increase over time.
Most mortality studies are based on record linkage. People with schizophrenia are identified via psychiatric case registers and then subsequently linked to registers of cause of death. Some studies13,22 report mortality ratios based on hospital inpatient cohorts. Other studies23,24 have used community-based follow-up data for people with schizophrenia who are first identified through community surveys and then followed up for extended periods.
Identification of studies
Guidelines outlined by the Meta-analysis of Observational Studies in Epidemiology25 were followed to identify and collate mortality studies. The broad search string of (schizo* or psych*) and (mortalityor outcomeorfollow-up) was used in MEDLINE, PsychINFO, Web of Science, and Google Scholar to identify all research studies that investigated mortality in schizophrenia. Potentially relevant articles (in all languages) were accessed to review the full text. Citations from significant articles and review articles were scrutinized to locate additional relevant articles, book chapters, and conference papers. The Web of Science Cited Reference Search system was also used to locate relevant articles. Finally, letters or e-mails were sent to the senior authors of articles that met the inclusion criteria. These authors were provided with an interim list of included studies and asked to nominate missing studies.
Inclusion and exclusion rules
Studies were included if they met all the following criteria: (1) published and/or available between January 1, 1980, and January 31, 2006, (2) reported deaths in people with schizophrenia as diagnosed by any criteria, (3) studied a population 15 years and older, (4) reported primary data on all-cause mortality and/or cause-specific mortality, and (5) reported SMRs and/or data on observed and expected deaths sufficient to calculate SMRs. Studies were excluded if they (1) involved people with a diagnosis other than schizophrenia (ie, studies that reported on broader categories of psychosis were excluded), (2) reported duplicate data, (3) reported SMRs solely attributable to suicide (this was the focus of a recent systematic review and meta-analysis3), and (4) reported mortality in subgroups of the population (eg, homeless people,26 twins,27 and those involved in clinical trials).
Once a study was included, data were extracted and entered into a 3-level, normalized database that included study-level variables (eg, authors, year of publication, and site), middle-level variables (eg, age group, recruitment duration, case-finding method, and diagnostic criteria), and estimate-level variables (eg, general and specific-cause SMRs for all persons, males, or females). Two or more of the authors checked all data used in the analysis. When disagreements arose, these were resolved by consensus. If required, we contacted the original authors for clarification of issues. The full data set is available from the authors (www.qcmhr.uq.edu.au/epi).
To assess the impact of overall quality of the distribution of SMRs, we devised a quality score. On the basis of operationalized criteria, this score rewarded studies that (1) used superior research design features (eg, more thorough case ascertainment, published diagnostic criteria, methods to confirm diagnosis, and longer periods of follow-up) and (2) provided comprehensive reporting of the study results (eg, provision of numerator, denominator, SMRs, details of subject attrition, and description of the completeness of the data source). Full details of the quality score used in this review are available from the authors (www.qcmhr.uq.edu.au/epi).
In systematic reviews, it is important to avoid double counting of the index variable (deaths) by the same or different studies. Thus, a key feature of this review is the application of sequential filters to identify discrete mortality estimates. We applied a similar sorting algorithm to that used in our previous reviews of schizophrenia.19,20 Briefly, the mortality estimates were sorted into different causes of death. Study-level and middle-level filters were applied to isolate data from multiple studies that overlapped in both time and place. The third filter was used to select 1 representative mortality estimate for inclusion in the cumulative distribution using the “most informative” rule. For example, if 1 study presented multiple overlapping ratios, the ratios based on the largest sample were preferred (ie, the widest age range was preferred over narrower age strata).
The highest-order (and most reliable) category of death, all-cause mortality, can be further subdivided according to rules such as those codified by the International Classification of Diseases, Ninth Revision (ICD-9).28 Almost all included studies in this review were coded with the ICD-9. Although death can result from the combination of many different health problems, in circumstances in which several codes may be suitable, emphasis is given to the underlying cause of death. More specific causes of death can be allocated to categories according to organ systems (eg, cardiovascular or gastrointestinal) or nature of disease (eg, cancers are coded together). Apart from codes for these specific domains, studies occasionally report SMRs for middle-level categories such as all-unnatural (ICD-9 codes E800-E999) (which includes codes for suicide, accident, and homicide) and all-natural (ICD-9 codes 001-799; the remainder from all-cause when all-unnatural cause is excluded).
The SMRs were extracted from the publications or calculated by dividing the sum of observed deaths by the sum of expected deaths (when sufficient data were available to calculate these). The distributions of SMRs were assessed in cumulative plots, with every SMR contributing to the distribution. The distribution of the data was assessed in rank order for SMRs (lowest to highest ranks) with the cumulative percentage of SMRs shown on the vertical axis. Key features of these distributions are presented (eg, median, mean, geometric mean, standard deviation, and quantiles at 10%, 25%, 50%, 75%, and 90%).
For all-cause death, we were often able to extract data on case fatality rate (CFR). The CFR is calculated by dividing the number of deaths in people with schizophrenia during a certain period by the number of people with that disorder at the beginning of the period. An annualized CFR was derived to allow comparisons among studies of different durations.14
In keeping with definitions from our previous systematic reviews of schizophrenia,20,29 we divided studies according to the per capita gross national product of the study site (based on 2004 data)30 and used a standard World Bank definition of country status31: (1) least developed countries, mean income of less than US $2995; (2) emerging economy countries, mean income between US $2995 and $9266; and (3) developed countries, mean income of greater than US $9266.
To assess secular trends, we used meta-regression to examine the relationship between the midpoint of the follow-up period and all-cause SMR for persons. Study quality scores were divided into tertiles, and the distribution of all-cause SMR for persons were compared according to these 3 levels.
We performed statistical analyses for the test of significance between distributions of different SMRs. These analyses take into account (1) the need to control for within-study variation (estimates drawn from the same study tend to be more alike than SMRs drawn from different studies) and (2) the use of a log transformation to analyze distributions that are often positively skewed. Analyses were performed with SAS statistical software, version 9.2 (SAS Institute Inc, Cary, North Carolina).
We also undertook a secondary analysis based on conventional meta-analytic techniques. Because SMRs are known to vary widely among sites because of population and disease frequency differences, we adopted a random-effects model to estimate a pooled SMR for all-cause mortality for persons.21 When necessary, 95% confidence intervals (CIs) were generated according to the formula detailed by Rothman and Greenland.21 Heterogeneity among the studies was tested using the Cochran heterogeneity statistic.32 Apart from the specific analyses related to sex differences, we restricted the analyses to persons to limit the number of planned comparisons. The funding source played no part in the design, analyses, writing, or submission of this study.
The electronic search identified 1726 articles, whereas manual reference checking identified an additional 26 references. We received responses from 16 authors, who provided an additional 11 references. Four articles from languages other than English were included after translation. Eleven studies33-43 were excluded because they completely overlapped with other included studies. Further details of the results of the search strategy and key features of the included studies are available from the authors (www.qcmhr.uq.edu.au/epi).
The systematic review identified 37 studies9,12,13,18,22-24,44-73 that provided data on 561 SMRs for different causes of deaths drawn from 25 different countries: Australia (n = 2),59,68 Brazil (n = 1),61 Bulgaria (n = 1),53 Canada (n = 3),50,51,65 China (n = 1),53 Columbia (n = 1),53 Czech Republic (n = 1),53 Denmark (n = 2),63,64 Finland (n = 3),18,22,23 France (n = 2),46,48 Germany (n = 1),57 Hong Kong (n = 1),53 India (n = 2),12,53 Indonesia (n = 1),58 Ireland (n = 2)53,62 Israel (n = 1),73 Italy (n = 2),60,67 Japan (n = 3),53,69,71 Norway (n = 1),52 Russia (n = 1),53 Sweden (n = 2),9,66 Taiwan (n = 1),49 the Netherlands (n = 1),13 the United Kingdom (n = 5),44,47,53,54,56 and the United States (n = 6).24,45,53,55,70,72 The SMRs were based on an estimated total of 22 296 discrete deaths. Thirty-seven studies9,12,13,18,22-24,44-73 provided SMRs for all-cause mortality for either all persons, males, or females.
Figure 1 shows the distribution for all-cause SMRs for all persons, males, and females. The median all-cause SMR for all persons (based on 38 SMRs) was 2.58, with 10% and 90% quantiles ranging from 1.18 to 5.76 (Table 1). In other words, people with schizophrenia had 2.5 times the risk of dying compared with the general population, and the central 80% of all SMRs varied over a 4-fold range. The median annualized all-cause CFR for all persons was 95.4 per 10 000 population, with 10% and 90% quantiles ranging from 57.2 to 301.7 (5-fold range).
The median all-cause SMR for males (3.02) was slightly higher than females (2.37); however, these 2 distributions were not statistically significantly different (F1,18 = 0.0003; P = .99). For all persons, the median SMR for natural causes of death was 2.41, and the 10% and 90% quantiles ranged from 0.99 to 4.10 (Table 1). Elevated median SMRs were found in all of the specific causes of death apart from cerebrovascular diseases.
Seven studies18,47,49,51,56,65,66 published data for the summary category of unnatural causes of death for all persons, males, or females. Table 1 gives the distributions of SMRs for unnatural causes of death. People with schizophrenia had 12 times the risk of dying of suicide compared with the general population (median SMR, 12.86).
Twenty-two studies22,24,45-48,51,53-55,57,59,60,62,63,65-68,71-73 were identified that contributed 28 SMRs for developed countries, 3 studies53,58,61 contributed 6 SMRs for emerging economy countries, and 1 study53 contributed 4 SMRs for least developed countries. When divided according to this criterion, the all-cause SMR distributions were not significantly different (F2,34 = 0.30; P = .74); the median all-cause SMRs for least developed, emerging economy, and developed countries were 2.02, 2.19, and 2.79, respectively (Table 2).
When the all-cause SMRs for all persons were divided into study quality score tertiles, no significant differences were found between SMR distributions (F2,24 = 0.61; P = .55). On the basis of follow-up periods, we identified 8 studies24,45,51,54,55,63,71,72 with SMRs from the 1970s, 10 studies47,53,57-60,65-67,73 with SMRs from the 1980s, and 7 studies22,46,48,53,61,62,68 with SMRs from the 1990s. Concerning secular change, meta-regression confirmed a significant positive association between the follow-up period midpoint year and all-cause SMR (slope coefficient, 0.06; 95% CI, 0.01-0.11; z = 2.21; P = .03). The median SMRs for the 1970s, 1980s, and 1990s were 1.84, 2.98, and 3.20, respectively. Concerning CFRs, the median rates per 10 000 population (all-cause mortality) were 162.2, 95.4, and 108.3 for the 1970s, 1980s, and 1990s, respectively. The CFRs for the 3 decades were not statistically significantly different (F2,23 = 0.38; P = .38).
The 38 studies that report all-cause SMRs for all persons are shown in a traditional forest plot with a pooled estimate based on a random-effects model in Figure 2. Using traditional meta-analytic techniques, we found that the pooled random-effects all-cause SMR (based on 37 SMRs with finite standard errors) for all persons was 2.50 (95% CI, 2.18-2.83). The Cochran Q test found a marginally acceptable level of heterogeneity (Q36 = 50.72; P = .06). We undertook several post hoc analyses to explore potential sources of variation (eg, published vs unpublished diagnostic criteria, cohorts based on first-episode patients vs all patients, cohorts based on inpatient and/or outpatient samples, sites clustered according to World Health Organization regions, and SMRs attributable to suicide sorted by decade). However, none of the post hoc comparisons resulted in significantly different SMR distributions (data not shown).
People with schizophrenia have a substantially increased risk of death compared with the general population. Overall, people with schizophrenia have 2.5 times the risk of dying. This review was able to extract data from 37 studies that were conducted in 25 countries. As predicted, the distribution of all-cause SMRs showed prominent variability.
Confirming the hypothesis that the relative mortality risk associated with schizophrenia is increasing, we found that SMRs have increased in a linear fashion during the 3 decades examined in this study. This finding is consistent with earlier studies.4,17 Considering that (1) CFRs for schizophrenia did not significantly differ among the decades and (2) age-standardized mortality rates are generally decreasing in most nations,74-76 these findings suggest that people with schizophrenia have not fully benefited from the improvements in health outcomes available to the general population. The SMRs are ratio measures and thus reflect differential mortality. If mortality rates in the general population decrease over time at a faster rate than those for people with schizophrenia, then SMRs for people with schizophrenia will increase over time. The evidence from the current study suggests that this differential mortality gap has widened over time.
Mental health services have advanced in many parts of the world during the past few decades. Apart from a different mix of community-based care, the introduction of the second-generation antipsychotic medications in the early 1990s was initially found to be associated with better quality of life and reduced risk of relapse.77-79 More recent trials have questioned the clinical superiority of second-generation antipsychotic medication,80,81 and concern is now widespread about the adverse effects associated with these medications.82 In particular, compared with typical antipsychotics, several of the second-generation antipsychotics are more likely to cause weight gain and metabolic syndrome.83 Because the metabolic syndrome is associated with a 2- to 3-fold increase in cardiovascular mortality and a 2-fold increase in all-cause mortality,84 these adverse effects would be expected to contribute to even higher SMRs in the next few decades.85,86 Unfortunately, we are unable to explore the role of atypical medications as a contributing factor for the increasing SMRs associated with schizophrenia (eg, deaths related to clozapine-induced agranulocytosis or deaths related to atypical antipsychotic-induced weight gain). Adverse health outcomes associated with weight gain and/or metabolic syndrome (eg, myocardial infarction, cerebrovascular accidents, or cancer) may take decades to fully emerge. Thus, it seems likely that studies undertaken in the 1990s (ie, the most recent studies included in this review) would capture only a small fraction of the eventual burden of mortality associated with the adverse effect profile of the second-generation antipsychotic medications. In light of the rising secular trends in SMRs already identified by this review, the prospect of further increases in mortality risks for schizophrenia is alarming.
In keeping with the findings of Harris and Barraclough11 and Simpson,10 we found no significant sex difference in all-cause SMRs. Thus, although many well-documented sex differences exist in the epidemiological features of schizophrenia,19,87,88 the increased risk of mortality associated with schizophrenia affects men and women equally.
Of the specific-cause SMRs, suicide was associated with the highest estimate: 12 times greater than expected from the general population. In keeping with previous reviews, the SMRs associated with many different types of natural causes of death were elevated in people with schizophrenia. Curiously, the category neoplastic disorder had one of the lowest median SMRs (1.37). Although the median was still greater than 1, several record linkage studies89 have suggested that cancers may be significantly less prevalent in people with schizophrenia. The current review examines only mortality, and studies that examine morbidity would be better able to explore this issue.90
We found no significant difference in SMRs among sites when sorted by economic status. However, this meta-analysis identified just 3 studies53,58,61 that provided discrete SMRs from the least developed and emerging economy countries; thus, caution should be exercised in the interpretation of this finding. Furthermore, a single derived variable was used to define economic status, which was applied at the ecological level.
What factors have contributed to the differential mortality risk associated with schizophrenia? Many demographic, clinical, political, and cultural factors mediate pathways and barriers to health care in general (eg, availability of services, stigma, and disease profiles).91 With respect to schizophrenia, the onset of the illness can result in a cascade of unhealthy lifestyle factors that elevate the risk of various somatic diseases and consequently increase the risk of death. People with schizophrenia are thought to be less inclined to seek health care, to consume less medical care, to engage in high-risk behaviors, and to be less compliant with their treatments.82,90,92 However, in addition to factors that operate on the pathway to care, schizophrenia and its associated comorbid somatic conditions may be downstream expressions of common genetic or environmental factors.92,93 For example, it is feasible that polymorphisms in genes may increase the susceptibility to both schizophrenia and diabetes94 or that de novo germline mutations across many generations could result in an increased risk of schizophrenia95 and a wide range of adverse health outcomes. Prenatal nutritional disruptions may equally affect brain development and general metabolic functioning.96,97 Although the current review cannot address these issues directly, the worsening SMRs associated with schizophrenia noted in recent decades suggest that this already disadvantaged group is not benefiting from the improved health of the community in an equitable fashion. A systematic approach to monitoring and treating the physical health needs of people with schizophrenia is clearly warranted.98
Several important caveats to this review should be noted. Publication bias is always an issue in systematic reviews. We endeavored to address this by obtaining data from all available sources, including those from electronic databases, citations and authors, and publications in languages other than English. Factors such as the reliability of psychiatric diagnoses and admission practices (between sites and across time) could contribute to the variability identified in this systematic review. The reliability of the categorization of cause of death is also a cause for concern. With respect to specific-cause mortality, changes in the coding rules for the ICD-9 and between-site variability in the application of these rules also need to be taken into account.99,100 However, these issues do not affect all-cause SMRs (which were used for the main analyses in this review). The current study found a higher all-cause SMR (median SMR, 2.58; pooled meta-analysis SMR, 2.50) compared with the 2 previous reviews, which reported all-cause SMRs of 1.514 and 1.57.11 The 2 previous systematic reviews were based on studies published before 199511 and 19964 compared with the current systematic review, which included 18 additional studies published after 1995.
In conclusion, compared with the general population, people with schizophrenia have a 2- to 3-fold increased risk of dying. Suicide contributes to the increased mortality associated with schizophrenia; however, people with schizophrenia have increased mortality risks attributable to a wide range of somatic conditions. The increased mortality risk affects both sexes equally. Substantial variation occurs in all-cause SMRs among sites. In recent decades, the differential mortality gap associated with schizophrenia has been increasing. It is sobering to reflect on this paradox of schizophrenia treatment. As we become better at detecting and treating the core symptoms of schizophrenia, patients have worsening SMRs. Given the potential for an even greater disease burden as a result of the introduction of second-generation antipsychotic medications, research aimed at optimizing the physical health of people with schizophrenia needs to be undertaken with a sense of urgency.
Correspondence: John McGrath, MD, PhD, FRANZCP, Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol Q4076, Australia (john_mcgrath@qcmhr.uq.edu.au).
Submitted for Publication: November 4, 2006; final revision received January 16, 2007; accepted March 12, 2007.
Author Contributions: Mr Saha has full access to all of the data in the study and takes responsibility for the integrity of the data.
Financial Disclosure: None reported.
Funding/Support: The Stanley Medical Research Institute supported this project.
Additional Information: The following additional material is available at www.qcmhr.uq.edu.au/epi: Figure S1: Flow Diagram (Selection Strategy) of Included Studies in the Mortality of Schizophrenia; Table S2: Quality Reporting Scale; Table S3: Summary Table of All-Cause Mortality and Standardized Mortality Ratio for Schizophrenia (1980-2006); Table S4: Standardized Mortality Ratios (SMRs) for Schizophrenia by Different Causes of Death for Males and Females; Table S5: Standardized Mortality Ratios for 3 Quality Score Tertiles of All-Cause Death; Table S6: Standardized Mortality Ratios for Schizophrenia of All-Cause Mortality for Various Post Hoc Analyses (for All Persons); and Microsoft Excel spreadsheet of the primary data for this systematic review, plus associated labels and formats.
Additional Contributions: Dozens of researchers from around the world assisted in locating the data for this systematic review, and the staff of the Queensland Centre for Mental Health Research assisted in extracting the data and preparing the original manuscript.
1.Murray
CJLopez
AD Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study.
Lancet 1997;349
(9063)
1436- 1442
PubMedGoogle ScholarCrossref 2.Murray
CJLopez
AD Mortality by cause for eight regions of the world: Global Burden of Disease Study.
Lancet 1997;349
(9061)
1269- 1276
PubMedGoogle ScholarCrossref 3.Palmer
BAPankratz
VSBostwick
JM The lifetime risk of suicide in schizophrenia: a reexamination.
Arch Gen Psychiatry 2005;62
(3)
247- 253
PubMedGoogle ScholarCrossref 5.Graunt
J Natural and political observations mentioned in a following index, and made upon the bills of mortality. Hunter
RAMacAlpine
Ieds
Three Hundred Years of Psychiatry 1538-1860. London, England Oxford University Press1963;1662- 1666
Google Scholar 6.Kraepelin
E Dementia Praecox and Paraphrenia. Edinburgh, Scotland Livingstone1919;
7.Alstrom
CH Mortality in mental hospitals with special regard to tuberculosis.
Acta Psychiatr Neurol Scand Suppl 1942;24
Google Scholar 8.Bleuler
E Dementia Paecox or the Group of Schizophrenias. New York, NY International University Press1950;
10.Simpson
JC Mortality studies in schizophrenia. Tsuang
MTSimpson
JCeds
Handbook of Schizophrenia, Volume 3: Nosology, Epidemiology and Genetics of Schizophrenia. Amsterdam, the Netherlands Elsevier1988;245- 274
Google Scholar 12.Dube
KCKumar
NDube
S Long term course and outcome of the Agra cases in the International Pilot Study of Schizophrenia.
Acta Psychiatr Scand 1984;70
(2)
170- 179
PubMedGoogle ScholarCrossref 14.Murray
CJLopez
ADJamison
DT The global burden of disease in 1990: summary results, sensitivity analysis and future directions.
Bull World Health Organ 1994;72
(3)
495- 509
PubMedGoogle Scholar 15.Department of Health and Ageing, National Mental Health Report 2005: Summary of Ten Years of Reform in Australia's Mental Health Services Under National Mental Health Strategy 1993-2003. Canberra Commonwealth of Australia2005;
16.World Health Organization, The World Health Report 2001: Mental Health: New Understanding, New Hope. Geneva, Switzerland World Health Organization2001;
17.Osby
UCorreia
NBrandt
LEkbom
ASparen
P Time trends in schizophrenia mortality in Stockholm County, Sweden: cohort study.
BMJ 2000;321
(7259)
483- 484
PubMedGoogle ScholarCrossref 18.Heilä
HHaukka
JSuvisaari
JLonnqvist
J Mortality among patients with schizophrenia and reduced psychiatric hospital care.
Psychol Med 2005;35
(5)
725- 732
PubMedGoogle ScholarCrossref 19.McGrath
JSaha
SWelham
JEl Saadi
OMacCauley
CChant
D A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology.
BMC Med 2004;2
(1)
13
PubMedGoogle ScholarCrossref 21.Greenland
S Meta-analysis. Rothman
KJGreenland
Seds
Modern Epidemiology. 2nd Sydney, Australia Lippincott Williams & Wilkins1998;643- 674
Google Scholar 22.Räsänen
SHakko
HViilo
KMeyer-Rochow
VBMoring
J Excess mortality among long-stay psychiatric patients in Northern Finland.
Soc Psychiatry Psychiatr Epidemiol 2003;38
(6)
297- 304
PubMedGoogle Scholar 23.Joukamaa
MHeliovaara
MKnekt
PAromaa
ARaitasalo
RLehtinen
V Mental disorders and cause-specific mortality.
Br J Psychiatry 2001;179498- 502
PubMedGoogle ScholarCrossref 24.Martin
RLCloninger
CRGuze
SBClayton
PJ Mortality in a follow-up of 500 psychiatric outpatients 1: total mortality.
Arch Gen Psychiatry 1985;42
(1)
47- 54
PubMedGoogle ScholarCrossref 25.Stroup
DFBerlin
JAMorton
SCOlkin
IWilliamson
GDRennie
DMoher
DBecker
BJSipe
TAThacker
SBMeta-analysis Of Observational Studies in Epidemiology (MOOSE) Group, Meta-analysis of observational studies in epidemiology: a proposal for reporting.
JAMA 2000;283
(15)
2008- 2012
PubMedGoogle ScholarCrossref 26.Babidge
NCBuhrich
NButler
T Mortality among homeless people with schizophrenia in Sydney, Australia: a 10-year follow-up.
Acta Psychiatr Scand 2001;103
(2)
105- 110
PubMedGoogle ScholarCrossref 29.Saha
SWelham
JChant
DMcGrath
J Incidence of schizophrenia does not vary with economic status of the country: evidence from a systematic review.
Soc Psychiatry Psychiatr Epidemiol 2006;41
(5)
338- 340
PubMedGoogle ScholarCrossref 31.Soubbotina
TP Beyond Economic Growth: An Introduction to Sustainable Development. 2nd Washington, DC World Bank2004;
33.Allebeck
PWistedt
B Mortality in schizophrenia: a ten-year follow-up based on the Stockholm County inpatient register.
Arch Gen Psychiatry 1986;43
(7)
650- 653
PubMedGoogle ScholarCrossref 34.Amaddeo
FBisoffi
GBonizzato
PMicciolo
RTansella
M Mortality among patients with psychiatric illness: a ten-year case register study in an area with a community-based system of care.
Br J Psychiatry 1995;166
(6)
783- 788
PubMedGoogle ScholarCrossref 35.Baxter
DN The mortality experience of individuals on the Salford Psychiatric Case Register, I: all-cause mortality.
Br J Psychiatry 1996;168
(6)
772- 779
PubMedGoogle ScholarCrossref 37.Buda
MTsuang
MTFleming
JA Causes of death in DSM-III schizophrenics and other psychotics (atypical group): a comparison with the general population.
Arch Gen Psychiatry 1988;45
(3)
283- 285
PubMedGoogle ScholarCrossref 38.D'Avanzo
BLa Vecchia
CNegri
E Mortality in long-stay patients from psychiatric hospitals in Italy: results from the Qualyop Project.
Soc Psychiatry Psychiatr Epidemiol 2003;38
(7)
385- 389
PubMedGoogle Scholar 39.Montout
CCasadebaig
FLagnaoui
RVerdoux
HPhilippe
ABegaud
BMoore
N Neuroleptics and mortality in schizophrenia: prospective analysis of deaths in a French cohort of schizophrenic patients.
Schizophr Res 2002;57
(2-3)
147- 156
PubMedGoogle ScholarCrossref 40.Ringbäck Weitoft
GGullberg
ARosen
M Avoidable mortality among psychiatric patients.
Soc Psychiatry Psychiatr Epidemiol 1998;33
(9)
430- 437
PubMedGoogle ScholarCrossref 42.Valenti
MNecozione
SBusellu
GBorrelli
GLepore
ARMadonna
RAltobelli
EMattei
ATorchio
PCorrao
GDi Orio
F Mortality in psychiatric hospital patients: a cohort analysis of prognostic factors.
Int J Epidemiol 1997;26
(6)
1227- 1235
PubMedGoogle ScholarCrossref 43.Waddington
JLYoussef
HAKinsella
A Mortality in schizophrenia: antipsychotic polypharmacy and absence of adjunctive anticholinergics over the course of a 10-year prospective study.
Br J Psychiatry 1998;173325- 329
PubMedGoogle ScholarCrossref 44.Anderson
CConnelly
JJohnstone
ECOwens
DGC Cause of death.
Br J Psychiatry Suppl 1991;13
(13)
((suppl 13))
30- 33
PubMedGoogle Scholar 45.Black
DW Mortality in schizophrenia: the Iowa Record-Linkage Study: a comparison with general population mortality.
Psychosomatics 1988;29
(1)
55- 60
PubMedGoogle ScholarCrossref 46.Bralet
MCYon
VLoas
GNoisette
C Mortality in schizophrenia: a 8-year follow-up study in 150 chronic schizophrenics.
Encephale 2000;26
(6)
32- 41
PubMedGoogle Scholar 48.Casadebaig
FPhilippe
A Mortality among schizophrenic patients.
Encephale 1999;25
(4)
329- 337
PubMedGoogle Scholar 50.Curkendall
SMMo
JGlasser
DBRose Stang
MJones
JK Cardiovascular disease in patients with schizophrenia in Saskatchewan, Canada.
J Clin Psychiatry 2004;65
(5)
715- 720
PubMedGoogle ScholarCrossref 53.Harrison
GHopper
KCraig
TLaska
ESiegel
CWanderling
JDube
KCGanev
KGiel
Ran der Heiden
WHolmberg
SKJanca
ALee
PWLeón
CAMalhotra
SMarsella
AJNakane
YSartorius
NShen
YSkoda
CThara
RTsirkin
SJVarma
VKWalsh
DWiersma
D Recovery from psychotic illness: a 15- and 25-year international follow-up study.
Br J Psychiatry 2001;178506- 517
PubMedGoogle ScholarCrossref 54.Hassall
CPrior
PCross
KW A preliminary study of excess mortality using a psychiatric case register.
J Epidemiol Community Health 1988;42
(3)
286- 289
PubMedGoogle ScholarCrossref 55.Haugland
GCraig
TJGoodman
ABSiegel
C Mortality in the era of deinstitutionali-zation.
Am J Psychiatry 1983;140
(7)
848- 852
PubMedGoogle Scholar 56.Herrman
HEBaldwin
JAChristie
D A record-linkage study of mortality and general hospital discharge in patients diagnosed as schizophrenic.
Psychol Med 1983;13
(3)
581- 593
PubMedGoogle ScholarCrossref 57.Hewer
WRossler
W Mortality of patients with functional psychiatric illnesses during inpatient treatment [in German].
Fortschr Neurol Psychiatr 1997;65
(4)
171- 181
PubMedGoogle ScholarCrossref 58.Kurihara
TKato
MKashima
HTakebayashi
TReverger
RTirta
IGR Excess mortality of schizophrenia in the developing country of Bali.
Schizophr Res 2006;83
(1)
103- 105
PubMedGoogle ScholarCrossref 59.Lawrence
DJablensky
AVHolman
CDJPinder
TJ Mortality in Western Australian psychiatric patients.
Soc Psychiatry Psychiatr Epidemiol 2000;35
(8)
341- 347
PubMedGoogle ScholarCrossref 60.Lesage
ADTrapani
VTansella
M Excess mortality by natural causes of Italian schizophrenic patients.
Eur Arch Psychiatry Neurol Sci 1990;239
(6)
361- 365
PubMedGoogle ScholarCrossref 61.Menezes
PRMann
AH Mortality among patients with non-affective functional psychoses in a metropolitan area of south-eastern Brazil.
Rev Saude Publica 1996;30
(4)
304- 309
PubMedGoogle ScholarCrossref 62.Morgan
MGScully
PJYoussef
HAKinsella
AOwens
JMWaddington
JL Prospective analysis of premature mortality in schizophrenia in relation to health service engagement: a 7.5-year study within an epidemiologically complete, homogeneous population in rural Ireland.
Psychiatry Res 2003;117
(2)
127- 135
PubMedGoogle ScholarCrossref 63.Mortensen
PBJuel
K Mortality and causes of death in schizophrenic patients in Denmark.
Acta Psychiatr Scand 1990;81
(4)
372- 377
PubMedGoogle ScholarCrossref 65.Newman
SCBland
RC Mortality in a cohort of patients with schizophrenia: a record linkage study.
Can J Psychiatry 1991;36
(4)
239- 245
PubMedGoogle Scholar 66.Osby
UCorreia
NBrandt
LEkbom
ASparen
P Mortality and causes of death in schizophrenia in Stockholm County, Sweden.
Schizophr Res 2000;45
(1-2)
21- 28
PubMedGoogle ScholarCrossref 67.Politi
PPiccinelli
MKlersy
CMadini
SSegagni
LGFratti
CBarale
F Mortality in psychiatric patients 5 to 21 years after hospital admission in Italy.
Psychol Med 2002;32
(2)
227- 237
PubMedGoogle ScholarCrossref 68.Ruschena
DMullen
PEBurgess
PCordner
SMBarry-Walsh
JDrummer
OHPalmer
SBrowne
CWallace
C Sudden death in psychiatric patients.
Br J Psychiatry 1998;172331- 336
PubMedGoogle ScholarCrossref 69.Saku
MTokudome
SIkeda
MKono
SMakimoto
KUchimura
HMukai
AYoshimura
T Mortality in psychiatric patients, with a specific focus on cancer mortality associated with schizophrenia.
Int J Epidemiol 1995;24
(2)
366- 372
PubMedGoogle ScholarCrossref 71.Tsuzuki
HYuasa
S An epidemiological study of deaths in mental hospitals [author's transl] [in Japanese].
Seishin Shinkeigaku Zasshi 1981;83
(5)
275- 304
PubMedGoogle Scholar 72.Wood
JBEvenson
RCCho
DWHagan
BJ Mortality variations among public mental health patients.
Acta Psychiatr Scand 1985;72
(3)
218- 229
PubMedGoogle ScholarCrossref 73.Zilber
NSchufman
NLerner
Y Mortality among psychiatric patients–the groups at risk.
Acta Psychiatr Scand 1989;79
(3)
248- 256
PubMedGoogle ScholarCrossref 74.Wamala
SBlakely
TAtkinson
J Trends in absolute socioeconomic inequalities in mortality in Sweden and New Zealand: a 20-year gender perspective.
BMC Public Health 2006;6164
PubMedGoogle ScholarCrossref 75.Murray
CJLopez
AD Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study.
Lancet 1997;349
(9064)
1498- 1504
PubMedGoogle ScholarCrossref 76.Jemal
AWard
EHao
YThun
M Trends in the leading causes of death in the United States, 1970-2002.
JAMA 2005;294
(10)
1255- 1259
PubMedGoogle ScholarCrossref 77.Leucht
SBarnes
TRKissling
WEngel
RRCorrell
CKane
JM Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials.
Am J Psychiatry 2003;160
(7)
1209- 1222
PubMedGoogle ScholarCrossref 78.Leucht
SWahlbeck
KHamann
JKissling
W New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis.
Lancet 2003;361
(9369)
1581- 1589
PubMedGoogle ScholarCrossref 79.Awad
AGVoruganti
LN Impact of atypical antipsychotics on quality of life in patients with schizophrenia.
CNS Drugs 2004;18
(13)
877- 893
PubMedGoogle ScholarCrossref 80.Lieberman
JAStroup
TSMcEvoy
JPSwartz
MSRosenheck
RAPerkins
DOKeefe
RSDavis
SMDavis
CELebowitz
BDSevere
JHsiao
JK Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.
N Engl J Med 2005;353
(12)
1209- 1223
PubMedGoogle ScholarCrossref 81.Jones
PBBarnes
TRDavies
LDunn
GLloyd
HHayhurst
KPMurray
RMMarkwick
ALewis
SW Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1).
Arch Gen Psychiatry 2006;63
(10)
1079- 1087
PubMedGoogle ScholarCrossref 82.Hennekens
CHHennekens
ARHollar
DCasey
DE Schizophrenia and increased risks of cardiovascular disease.
Am Heart J 2005;150
(6)
1115- 1121
PubMedGoogle ScholarCrossref 83.Remington
G Schizophrenia, antipsychotics, and the metabolic syndrome: is there a silver lining?
Am J Psychiatry 2006;163
(7)
1132- 1134
PubMedGoogle ScholarCrossref 84.Lakka
HMLaaksonen
DELakka
TANiskanen
LKKumpusalo
ETuomilehto
JSalonen
JT The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men.
JAMA 2002;288
(21)
2709- 2716
PubMedGoogle ScholarCrossref 85.Allison
DBCasey
DE Antipsychotic-induced weight gain: a review of the literature.
J Clin Psychiatry 2001;62
((Suppl 7))
22- 31
PubMedGoogle Scholar 86.Fontaine
KRHeo
MHarrigan
EPShear
CLLakshminarayanan
MCasey
DEAllison
DB Estimating the consequences of anti-psychotic induced weight gain on health and mortality rate.
Psychiatry Res 2001;101
(3)
277- 288
PubMedGoogle ScholarCrossref 87.Aleman
AKahn
RSSelten
JP Sex differences in the risk of schizophrenia: evidence from meta-analysis.
Arch Gen Psychiatry 2003;60
(6)
565- 571
PubMedGoogle ScholarCrossref 88.Castle
DJ Sex differences in brain development, organisation and degeneration: are they relevant to sex differences in schizophrenia? Castle
DJMcGrath
JKulkarni
Jeds
Women and Schizophrenia. Cambridge, MA Cambridge University Press2000;5- 18
Google Scholar 89.Cohen
MDembling
BSchorling
J The association between schizophrenia and cancer: a population-based mortality study.
Schizophr Res 2002;57
(2-3)
139- 146
PubMedGoogle ScholarCrossref 90.Coghlan
RLawrence
DJablensky
A Duty to Care: Physical Illness in People with Mental Illness. Perth The University of Western Australia2001;
91.Murray
CJLopez
AD Global and regional cause-of-death patterns in 1990.
Bull World Health Organ 1994;72
(3)
447- 480
PubMedGoogle Scholar 93.Eaton
WWByrne
MEwald
HMors
OChen
CYAgerbo
EMortensen
PB Association of schizophrenia and autoimmune diseases: linkage of Danish national registers.
Am J Psychiatry 2006;163
(3)
521- 528
PubMedGoogle ScholarCrossref 94.Gough
SCO'Donovan
MC Clustering of metabolic comorbidity in schizophrenia: a genetic contribution?
J Psychopharmacol 2005;19
(6)
((suppl))
47- 55
PubMedGoogle ScholarCrossref 98.Marder
SREssock
SMMiller
ALBuchanan
RWCasey
DEDavis
JMKane
JMLieberman
JASchooler
NRCovell
NStroup
SWeissman
EMWirshing
DAHall
CSPogach
LPi-Sunyer
XBigger
JT
JrFriedman
AKleinberg
DYevich
SJDavis
BShon
S Physical health monitoring of patients with schizophrenia.
Am J Psychiatry 2004;161
(8)
1334- 1349
PubMedGoogle ScholarCrossref 99.World Health Organization, Manual of the Statistical International Classification of Diseases, Injuries, and Causes of Death, 1975 Revision. 1 Geneva, Switzerland World Heath Organization1977;
100.Goldacre
MJDuncan
MEGriffith
MCook-Mozaffari
P Psychiatric disorders certified on death certificates in an English population.
Soc Psychiatry Psychiatr Epidemiol 2006;41
(5)
409- 414
PubMedGoogle ScholarCrossref