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Heart disease treatment and mortality in schizophrenia and bipolar disorder – Changes in the danish population between 1994 and 2006
Journal of Psychiatric Research 45 (2011) 29e35
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Heart disease treatment and mortality in schizophrenia and bipolar disorder e Changes in the danish population between 1994 and 2006 Thomas Munk Laursen a, *, Merete Nordentoft b a b
National Center for Register-Based Research, University of Aarhus, Taasingegade 1, DK-8000 Aarhus C, Denmark Psychiatric Center Copenhagen, Copenhagen University, Faculty of Health Sciences, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 October 2009 Received in revised form 26 April 2010 Accepted 28 April 2010
Persons with schizophrenia and bipolar disorder have much higher heart disease mortality rates than the general population. The objective was to compare the general population with persons with schizophrenia, bipolar disorder or other psychiatric disorders in terms of rates of somatic hospitalization and invasive heart disease procedures, and in terms of heart disease mortality during the period 1994 to 2006. Survival analysis was used to analyze heart disease mortality and somatic care trends in a cohort of all persons residing in Denmark. During the study period, heart disease mortality rose significantly among persons with schizophrenia: compared with the general population, the rise in the mortality rate ratio equalled 1.12 (95% confidence interval (CI) 1.08e1.15) every second year. This was not the case for persons with bipolar disorder [1.02 (0.98e1.05), not significant] or other psychiatric disorders [1.00 (0.99e1.01), not significant]. The entire period saw a lower hospitalization rate and fewer invasive cardiac procedures among persons with schizophrenia than among the general population. The higher mortality (with increasing trends) from heart disease in persons with schizophrenia compared to the rest of the cohort members can be explained partly by low rates of invasive cardiac procedures. However, other reasons, such as antipsychotic-induced weight gain, primary prevention, and difficulty following smoking cessation advice could also be part of the explanation. The results call for a greater focus on improvement in somatic care and lifestyle factors for this group of patients. Ó 2010 Elsevier Ltd. All rights reserved.
Keywords: Schizophrenia Bipolar disorder Heart disease mortality
1. Introduction A review found elevated mortality from natural causes in persons with schizophrenia (standardized mortality ratio (SMR) 1.3) and bipolar affective disorder (SMR ¼ 1.5) (Harris and Barraclough, 1998), which was also found in Nordic register-based studies (Osby et al., 2001, 2000; Joukamaa et al., 2001; Mortensen and Juel, 1993; Laursen et al., 2007). It has been suggested that recent decades have seen a rising tendency in the excess mortality of schizophrenic patients (Saha et al., 2007). Heart disease is considered to be the most common cause of death in Western countries (Laursen, 2006; Hennekens et al., 2005), even if mortality from heart disease in general has declined. This decline has been attributed to improved lifestyle and better medical care (Johnsen et al., 2006; Newcomer and Hennekens, 2007). Patients with schizophrenia and bipolar affective have a higher mortality from cardiac disorders than the general population (Laursen et al., 2007),
* Corresponding author. Tel.: þ45 89426816; fax: þ45 89426813. E-mail address: [email protected] (T.M. Laursen). 0022-3956/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2010.04.027
which has recently been suggested to be attributable, among others, to such patients’ lower frequency of hospitalization for heart disease and lesser exposure to cardiac treatment (Laursen et al., 2009). The aim of the paper was to evaluate the change in heart disease related hospitalizations, invasive heart disease procedures and mortality rates in the Danish population from 1994 to 2006. This was done by comparing patients with schizophrenia, bipolar disorder or other psychiatric disorders with the general population. The main focus was to examine if a divergent development between schizophrenia and the general population was present. 2. Method 2.1. Study population and follow-up All persons residing in Denmark during the period 1994e2006 were identified from The Danish Civil Registration System (Pedersen et al., 2006). Among these, 93.4% have been born in Denmark (2009a). Only persons born in Denmark were selected as cohort members, since psychiatric and somatic illness status before
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arrival to Denmark was unknown. The follow-up began on 1st January 1994 or on the cohort member’s 15th birthday, whichever came last. The follow-up ended on 1st January 2007, at the day of death, the day of first admission with heart disease (when this was the outcome), or the day of emigration, whichever came first. Psychiatric and somatic status was diagnosed using the ICD8 (World Health Organization, 1971) classification system until 31st December 1993, and the ICD10 (World Health Organization, 1994) classification from 1st January 1994. The ICD 9 classification was not used in Denmark. Data on psychiatric hospitalizations of the entire Danish population were drawn from the Danish Central Psychiatric Case Register (Munk-Jorgensen and Mortensen, 1997). Patients with schizophrenia (ICD8: 295(exclusive 295.79), ICD10: F20) and bipolar disorder (ICD8: 296.39, 296.19 ICD10: F30, F31) and a group of the remaining psychiatric diagnoses were indentified. Persons were categorized as having schizophrenia/bipolar disorder or another psychiatric diagnosis from the date of their admission to a psychiatric hospital with such a diagnosis. Patients with a diagnosis of both schizophrenia and bipolar disorder (approximately 8% of the bipolar patients) were categorized as having schizophrenia from the day of first diagnosis of schizophrenia. Data on cardiac hospitalizations of the entire Danish population were drawn from the Danish National Hospital Register (Andersen et al., 1999) which was established in 1977 and which contains information on all Danish somatic inpatient hospital contacts. We used only the primary diagnosis of heart disease and registered only those admissions where persons were hospitalized. The definition of heart disease included the following diagnoses (ICD10: I00eI25, I27, I30eI52, ICD8: 390e429). Invasive procedures were defined as Coronary Artery Bypass Graft (CABG), code ¼ 300.09e302.41, KFNA e KFNF or Percutaneous Transluminal Coronary Angioplasty (PTCA), code ¼ 303.50, 303.54, 303.59, KFNG02, KFNG05. The NOMESCO classification of surgical procedures was used as from 1996 (Andersen et al., 1999). In 1994 and 1995, a national classification system was used (Danish National Board of health, 1988). All Danish citizens have access to public health care free of charge. There are no private psychiatric hospitals treating severe mental disorders, and invasive procedures for cardiovascular disorders are almost only carried out at hospitals managed by the regional health authorities. All persons admitted with a heart disease during the 17-year period preceding the study period, i.e. from 1977 to 1994, were excluded from the analysis of heart disease admissions and invasive procedures. This minimized the mixing of prevalent and incident cases in the follow-up period (1994e2006). After the 17-year “washout” period, we assumed all cases to be incident. Underlying causes of death were identified from the Cause of Death Register (Juel and Helweg-Larsen, 1999). We used the definitions of death by heart disease listed above.
(CIs) were used. Trends were analyzed over two-year intervals, except during the first period 1994e1996, where a three-year interval was used. For example, the period from 1999 to 2000 over 2001e2002 to 2003e2004 spanned two calendar periods, and the expected increase in the relative risk was calculated by raising the trend to the power 2. If three periods have elapsed, the expected increase was calculated by raising the trend to the power 3, and so on. The Aalen-Johansen method (Rosthoj et al., 2004) was used to estimate the absolute risk (probability) of receiving cardiac procedures within one year after the first heart disease admission. 3. Results 3.1. Mortality from heart disease During the study period from 1st January 1994 to 31st December 2006, a total of 4,818,168 (Fig. 1) persons were at risk of heart disease mortality. Among these, heart disease was the primary cause of death in 170,248 (Fig. 1). Among those who died from heart disease, 155,904 had not been hospitalized due to psychiatric disease. A total of 978 had been admitted to a psychiatric hospital with a diagnosis of schizophrenia, 876 with a diagnosis of bipolar disorder, and 12,528 with other psychiatric diagnoses. Among persons with no psychiatric disorder, the 2005e2006 rates of mortality from heart disease had dropped to approximately half (for both men and women) the level observed for the
2.2. Statistical analyses Incidence rates of heart disease mortality, heart disease admissions, and invasive procedure were analyzed using Poisson regression with the GENMOD procedure in SAS version 9.1 (SAS Institute Inc, Cary, NC). This method approximates a Cox regression (Andersen et al., 1993; Laird and Olivier, 1981). Outcome measures were denoted as mortality rate ratios (MRR), where death was the end-point of interest; and incidence rate ratios (IRR), where first heart disease admission or first invasive procedure within one year was the end-point. All IRRs or MRRs were adjusted for or stratified by gender, calendar time, and age. IRR and MRR were calculated by log-likelihood estimation, and Wald’s 95% confidence intervals
Fig. 1. Flowchart of number of persons under risk in the follow-up period (1994e2006) and number of cases. Number in bold are referred to in the text in the paper.
T.M. Laursen, M. Nordentoft / Journal of Psychiatric Research 45 (2011) 29e35
1994e1996 period (Table 1). The same trend was seen for persons with other psychiatric disorders than schizophrenia and bipolar disorder. Women with bipolar disorder experienced the same decline, which was also present among men, although to a lesser extent. No decline in heart disease mortality was observed among persons with schizophrenia (Table 1). Compared with persons who had never been admitted to a psychiatric hospital, the heart disease MRRs of individuals admitted to a psychiatric hospital with a diagnosis (including bipolar disorder) other than schizophrenia was approximately 1.5e2 times higher during the entire period, and no increases in tendencies were observed (Fig. 2). Inversely, there was a clear tendency toward an increasing MRR across the entire follow-up period among individual with schizophrenia, with a significantly increasing trend of 1.12 (1.08, 1.15) every second year. In the entire period 1994 to 2006 there was a 76% increase in the excess mortality. Persons with bipolar disorder had confidence intervals that overlapped with “other psychiatric disorders” during the entire period; whereas this was only true for persons with schizophrenia at the start of the follow-up period (Fig. 2). Compared directly with bipolar disorder, schizophrenia showed an increasing trend equalling 1.07 (1.02e1.13) every second year. The results did not differ when stratified according to gender, age (<60, 60e69, 70þ), and time since psychiatric admission (less than 1 year since psychiatric admission, 1e4 years, 5 þ years), and the clear, increasing tendency of MRRs among persons with schizophrenia was found for all age strata. 3.2. Admission with heart disease During follow-up, 340,035 (Fig. 1) persons were admitted to a hospital with a diagnosis of heart disease. Among these 318,207 had never had a psychiatric admission, 1173 had been admitted due to bipolar disorder, and 1283 due to schizophrenia, while 19,372 had been admitted with another psychiatric disorder. The IRRs of heart disease admission in persons with other psychiatric admissions remained at a stable level throughout the follow-up period 25%e30% above that of the reference population of persons never admitted to a psychiatric hospital (Fig. 3). Similarly, no increasing tendency was detected among persons with bipolar disorder. In contrast, among persons with schizophrenia there was a significant 1.07 (1.04e1.10) tendency measured in two-year steps to obtain more heart disease admissions during the follow-up period than
31
among the reference population (Fig. 3). Stratification by gender produced the same pattern in each stratum. Stratification by age also gave the same pattern, but admission IRRs were generally at a lower level among the older cohort members with a psychiatric disorder than among the reference group. 3.3. Invasive heart disease procedures A total of 51,518 (Fig. 1) cohortees had an invasive heart disease procedures performed within one year of their first heart disease admission. Among these, 101 had schizophrenia, 127 bipolar disorder, and 2382 were admitted for other psychiatric disorders. The incidence of first heart disease procedure in the entire cohort rose by 40% (95% CI 40e41%) every second year during the followup period. Compared with the non-psychiatric part of the cohort, no significant trends in the development of invasive procedures were found among the 3 psychiatric disorders (Fig. 4). In the absence of changes in trends over calendar periods, we calculated the average IRR of invasive heart disease procedures for the entire follow-up period: cohort members with schizophrenia had an average IRR of 0.38 (0.31e0.46), while patients with bipolar disorder had an IRR of 0.63 (0.53e0.75) and patients with other psychiatric disorders an IRR of 0.70 (0.67e0.73), results not shown in Table or Figure. Among cohort members with schizophrenia, the probability of being subjected to invasive heart disease procedures rose from 2.8% in the first half of the follow-up (1994e1999) to 11.0% in the second half (2000e2006). The probability rose from 4.1% to 15.8% in cohortees with bipolar disorder and from 5.4% to 18.1% in persons with other psychiatric disorders, and no psychiatric admissions from 7.3% to 22.7% (results not shown in Table or Figure). 4. Discussion 4.1. Key findings During the period 1994e2006, heart disease mortality declined both in the population without psychiatric admissions and among persons with bipolar disorder and other psychiatric admissions; but these two groups had a higher mortality than the general population. In contrast, persons with schizophrenia had high and
Table 1 Number of heart disease deaths and mortality rates per 1000 person years at risk, stratified by psychiatric status. Adjusted for age, with age ¼ 65 as the reference group. Schizophrenia a
Mortality
Year
N
Women 94e96d 97e98 99e00 01e02 03e04 05e06
109 68 69 76 67 66
4.16 3.94 3.98 4.30 3.90 3.85
Men 94e96d 97e98 99e00 01e02 03e04 05e06
112 66 81 74 97 112
11.20 10.06 12.14 10.72 13.62 12.59
a
b
(3.39, (3.06, (3.10, (3.39, (3.03, (2.98,
5.10) 5.06) 5.11) 5.47) 5.02) 4.96)
(9.24, 13.58) (7.86, 12.87) (9.70, 15.19) (8.49, 13.54) (11.09, 16.73) (10.21, 15.53)
Bipolar disorderc
Other psych. adm.
No psych. adm.
Na
Mortalityb
Na
Na
Mortalityb
131 86 85 88 64 71
4.57 3.72 3.35 3.28 2.37 2.51
(3.78, (2.96, (2.67, (2.62, (1.83, (1.96,
5.53) 4.66) 4.21) 4.11) 3.07) 3.2)
1782 1134 1050 1124 936 863
3.70 3.27 2.84 2.91 2.35 2.11
(3.37, (2.96, (2.57, (2.63, (2.12, (1.90,
4.06) 3.62) 3.15) 3.21) 2.61) 2.35)
20,638 12,128 12,155 11,545 10,262 8914
2.15 1.85 1.82 1.70 1.50 1.28
(1.97, (1.70, (1.67, (1.56, (1.38, (1.17,
2.33) 2.01) 1.98) 1.85) 1.63) 1.39)
78 55 38 57 69 54
9.51 9.33 6.01 8.40 9.67 7.21
(7.58, (7.12, (4.36, (6.44, (7.59, (5.50,
11.95) 12.21) 8.30) 10.94) 12.31) 9.46)
1392 889 914 869 872 703
10.45 9.42 9.02 8.14 7.93 6.10
(9.70, (8.66, (8.30, (7.48, (7.29, (5.57,
11.25) 10.24) 9.80) 8.85) 8.63) 6.68)
22,712 13,360 12,459 11,919 10,517 9295
5.82 5.07 4.65 4.35 3.76 3.23
(5.51, (4.79, (4.40, (4.12, (3.55, (3.05,
6.14) 5.35) 4.91) 4.60) 3.97) 3.41)
Mortalityb
N ¼ number of heart disease deaths. Mortality rate per 1000 person years, adjusted for age with the reference group ¼ 65 years old. Thus, the mortality rates can be interpreted as the mortality rate for a 65-year-old person. c Approximately 8% of bipolar patients also had a diagnosis of schizophrenia, and they were categorized as having a schizophrenia diagnosis. d Note: 3-year group. b
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Fig. 2. Mortality rate ratio (MRR) of heart disease mortality among persons with schizophrenia, bipolar disorder, and other psychiatric disorders, compared with persons with no psychiatric admissions (reference group). Men and women combined. MRR, adjusted for age and gender. Vertical lines represent 95% confidence limits (CI). Non-overlapping CI indicates significant different MRR. Test for trends, measured in 2-year steps: Schizophrenia: 1.12 (1.08, 1.15) p < 0.0001; Bipolar disorder: 1.02 (0.98, 1.05) p ¼ 0.40; Other psych. adm.: 1.00 (0.99, 1.01) p ¼ 0.52; Never admitted: Reference.
stable rates of heart disease mortality throughout the entire period, causing the mortality gap between this group and the other groups to widen. Though their mortality remained stable, persons with schizophrenia had slightly higher and increasing rates of admission for heart diseases than the other groups. The rates of invasive heart disease procedures were lower among persons with bipolar disorder than among the general population, and particularly low among persons with schizophrenia throughout the entire period.
4.2. Why is there a mortality gap? Unhealthy lifestyle (Brown et al., 1999), increased smoking (Itkin et al., 2001; Dalack et al., 1998; Goff et al., 2005), and antipsychoticinduced weight gain(Allison et al., 1999; Daumit et al., 2008) in persons with schizophrenia have been established as probable reasons for excess mortality, although a recent study from Finland showed that the use of antipsychotic drugs was associated with lower mortality (Tiihonen et al., 2009).
Fig. 3. Incidence rate ratio (IRR) of heart disease admission among persons with schizophrenia, bipolar disorder, and other psychiatric disorders, compared with persons with no psychiatric admissions (reference group). Men and women combined. IRR, adjusted for age and gender. Vertical lines represent 95% confidence limits (CI). Non-overlapping CI indicates significant different MRR. Test for trends, measured in 2-year steps: Schizophrenia: 1.07 (1.04, 1.10) p < 0.0001; Bipolar disorder: 1.02 (0.99, 1.05) p ¼ 0.29; Other psych. adm.: 1.00 (1.00, 1.01) p ¼ 0.45; Never admitted: Reference.
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Fig. 4. Incidence rate ratio (IRR) of invasive heart disease procedure within one year after first heart disease admission among persons with schizophrenia, bipolar disorder, and other psychiatric disorders, compared with persons with no psychiatric admissions (reference group). Men and women combined. IRR, adjusted for age and gender. Vertical lines represent 95% confidence limits (CI). Non-overlapping CI indicates significant different MRR. Note: 1994e96 and 1997e98 is collapsed into one group because of few cases. Test for trends, measured in 2-year steps (except first 5 years): Schizophrenia: 1.03 (0.91, 1.17) p ¼ 0.65; Bipolar disorder: 1.04 (0.94, 1.16) p ¼ 0.43; Other psych. adm.: 1.00 (0.97, 1.02) p ¼ 0.73; Never admitted: Reference.
Physical health is poorer among persons with psychiatric disorders than among the general population. This also contributes to excess mortality in general and mortality from heart disease in particular (Kemp et al., 2009). In a study using Danish data (Laursen et al., 2009) similar to the data used in this study, less somatic hospitalization than needed and less use of invasive heart disease procedures among persons with severe mental disorder (schizophrenia, schizoaffective disorder, and bipolar disorder) than among the general population were suggested as additional reasons for their excess mortality. The same conclusion was reached in a study using Australian data (Lawrence and Coghlan, 2002), where rates of invasive heart disease procedures were also found to be lower in persons with mental disorders. A Finnish study (Rasanen et al., 2007), however, found no support for the theory of under-treatment of somatic diseases in patients with schizophrenia. A low socio-economic status has been associated with a negative impact on rates of death by heart disease (Pocock et al., 1987), and since persons with schizophrenia tend to have lower socioeconomic status (Byrne et al., 2004), some of the excess mortality could thus stem from this association. A mortality gap is present, and the literature suggests that the gap can be at least partly explained by known factors. However, our study also suggests that health inequalities have become even greater during the past decade among persons with schizophrenia. 4.3. Why has the mortality gap expanded? The mortality rate from heart disease remained at a high, stable level throughout the follow-up period in persons with schizophrenia. In contrast, it decreased in all the other sub-populations examined. This indicates that persons with schizophrenia are a particularly vulnerable group of patients, and that active measures should be established to ensure that they will also benefit from the general decline in heart disease mortality. Persons with schizophrenia often encounter discrimination in many areas of their lives (Thornicroft et al., 2009), and insufficient somatic care, as
measured in this paper, seems to be yet another barrier to be overcome. We hypothesize that the mortality gap has widened because patients with schizophrenia have not benefitted from recent therapeutic advances in cardiac therapy to the same extent as the general population which implies a comparative under-treatment of this group of vulnerable patients. The lack of the use of invasive procedures over a period of time will slowly become more and more visible in the cardiac death rates. The present analysis of our data does not allow us to determine whether the current under-treatment is due to patient or doctor behavior or both. It might be that patients were not thoroughly examined, or not referred to relevant treatment. Another possibility is that patients were non-compliant when somatic treatment was offered. However, both patient and doctor behavior can be addressed with flexible, need-based intervention. Our data indicate that this kind of care should be developed to decrease the mortality gap. The widening gap observed in the present study may also be rooted in factors that could not be examined in this study: In the general population, smoking cessation campaigns and smoking area restrictions have positively influenced smoking habits. Smoking decreased from 44% daily smokers in 1987e29% daily smokers in 2005 (2009b). We do not know these figures for patients with schizophrenia in Denmark, but one study has shown excess rates of smoking among persons with schizophrenia (Goff et al., 2005). One explanation for these excess rates could be that these patients found it more difficult to follow smoking cessation advice and to adopt more healthy lifestyle habits regarding diet and exercise than the general population. Finally, the study period saw the introduction of a range of antipsychotic drugs, primarily used in cases of schizophrenia, that have the metabolic syndrome as a possible side effect; it is possible that the introduction of these drugs has caused cardiac mortality to rise (Newcomer, 2007), thereby counteracting the generally positive development in heart disease mortality.
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The mortality rate is a marker of the general health status among persons with schizophrenia, and the lack of improvement in heart disease mortality underlines the need for more somatic care resources for this patient group. A non-optimal lifestyle with respect to avoiding health problems often leads to excess heart disease mortality; thus, a greater focus on lifestyle and help for persons with schizophrenia to successfully follow smoking cessation campaigns and specific programs encouraging their physical activity could probably help lower their excess mortality. Such general campaigns may have to be tailored to the specific needs of this particular patient group. This study shows that whichever initiatives are taken to help narrow the mortality gap in relation to the general population, efforts are needed to raise the level of somatic care e represented here by rates of somatic admission and invasive cardiac procedure e among patients with psychiatric diseases in general, and among persons with schizophrenia in particular. 4.4. Limitations Danish psychiatric care has become more outpatient-based during the past decades. Persons admitted to a psychiatric hospital may therefore be assumed to constitute an ever more selected fraction of psychiatric patients with particularly severe symptoms. To test this assumption, we also analyzed heart disease mortality, admissions, and invasive procedures in a set-up where we included psychiatric outpatients. Information on psychiatric outpatient contacts is only available as from 1995. When we included psychiatric outpatients, we found approximately 11% more persons with schizophrenia who died of a heart disease and 28% more cases with bipolar disorder; however, relative risks and invasive rates were almost identical to the numbers in Figs. 2e4, which suggests that this did not explain the results. We only had information on psychiatric admission from 1970 onwards. Thus, some of the older cohort members could have had a psychiatric admission before 1970 and no psychiatric admissions in the period 1970 to 2006. These persons would not be included in the group of persons with a psychiatric disorder. Persons with a more severe mental disorder have a greater probability of being readmitted; thus, a selection toward more severely ill persons among older cohort members could be expected. However, when we stratified for time since psychiatric admission, we found the same pattern, suggesting that this possible selection did not influence our results. 5. Conclusions The mortality rate from heart disease among persons with schizophrenia remained at a high, stable level throughout the follow-up period. In contrast, mortality rates decreased in the rest of the population. We found no improvement in the low levels of cardiac procedure among persons with schizophrenia during the follow-up period. This constant, low level could be a reason for the comparatively increased level of cardiac death among persons with schizophrenia. However, persons with schizophrenia could also have more difficulty following advice regarding lifestyle improvements, which typically results in higher heart disease mortality. Moreover, the introduction of a range of antipsychotic drugs, primarily for schizophrenia, with metabolic syndrome as a possible side effect during the time period examined may also have contributed to the lack of improvement in mortality. The mortality gap widened, probably due to a combination of the above-mentioned factors. This calls for a greater focus on improvement in somatic care and lifestyle factors for this group of
patients as it is hardly acceptable that persons with schizophrenia should not benefit from the general decrease in heart disease mortality. Role of funding source This study was supported by The Stanley Medical Research Institute. They had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Contributors Authors TML and MN designed the study and wrote the protocol. Author TML and MN managed the literature searches and analyses. Authors TML undertook the statistical analysis and had full access to all of the data in the study. Author TML takes responsibility for the integrity of the data and the accuracy of the data analyses. Author TML wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript. Declaration of interest None. Acknowledgments This study was supported by The Stanley Medical Research Institute. References Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. American Journal of Psychiatry 1999;156:1686e96. Andersen PK, Borgen Ø, Gill RD, Keiding N. Statistical models based on counting processes. Springer-Verlag; 1993. Andersen TF, Madsen M, Jorgensen J, Mellemkjoer L, Olsen JH. The danish national hospital register. A valuable source of data for modern health sciences. Danish Medical Bulletin 1999;46:263e8. Brown S, Birtwistle J, Roe L, Thompson C. The unhealthy lifestyle of people with schizophrenia. Psychological Medicine 1999;29:697e701. Byrne M, Agerbo E, Eaton WW, Mortensen PB. Parental socio-economic status and risk of first admission with schizophrenia- a Danish national register based study. Social Psychiatry and Psychiatric Epidemiology 2004;39:87e96. Dalack GW, Healy DJ, Meador-Woodruff JH. Nicotine dependence in schizophrenia: clinical phenomena and laboratory findings. American Journal of Psychiatry 1998;155:1490e501. Danish National Board of health, 1988. Classification of Surgical Procedure and Therapies Copenhagen. Daumit GL, Goff DC, Meyer JM, Davis VG, Nasrallah HA, McEvoy JP, et al. Antipsychotic effects on estimated 10-year coronary heart disease risk in the CATIE schizophrenia study. Schizophrenia Research 2008;105:175e87. Goff DC, Sullivan LM, McEvoy JP, Meyer JM, Nasrallah HA, Daumit GL, et al. A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls. Schizophrenia Research 2005;80:45e53. Harris EC, Barraclough B. Excess mortality of mental disorder. British Journal of Psychiatry 1998;173:11e53. Hennekens CH, Hennekens AR, Hollar D, Casey DE. Schizophrenia and increased risks of cardiovascular disease. American Heart Journal 2005;150:1115e21. Itkin O, Nemets B, Einat H. Smoking habits in bipolar and schizophrenic outpatients in southern Israel. Journal of Clinical Psychiatry 2001;62:269e72. Johnsen SP, Videbaek J, Pedersen L, Steffensen R, Videbaek R, Niemann T, et al. Survival trends among Danish patients undergoing coronary angiography for known or suspected ischaemic heart disease: a population based follow up study, 1992e2000. Heart 2006;92:27e31. Joukamaa M, Heliovaara M, Knekt P, Aromaa A, Raitasalo R, Lehtinen V. Mental disorders and cause-specific mortality. British Journal of Psychiatry 2001;179:498e502. Juel K, Helweg-Larsen K. The Danish registers of causes of death. Danish Medical Bulletin 1999;46:354e7. Kemp V, Bates A, Isaac M. Behavioural interventions to reduce the risk of physical illness in persons living with mental illness. Current Opinion in Psychiatry 2009;22:194e9.
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Pocock SJ, Shaper AG, Cook DG, Phillips AN, Walker M. Social class differences in ischaemic heart disease in British men. Lancet 1987;2:197e201. Rasanen S, Meyer-Rochow VB, Moring J, Hakko H. Hospital-treated physical illnesses and mortality: an 11-year follow-up study of long-stay psychiatric patients. European Psychiatry 2007;22:211e8. Rosthoj S, Andersen PK, Abildstrom SZ. SAS macros for estimation of the cumulative incidence functions based on a Cox regression model for competing risks survival data. Computer Methods and Programs in Biomedicine 2004;74:69e75. Statistics Denmark, accessed March 2009. http://www.dst.dk/. 2009a. b Sundheds- og sygeligheds undersøgelserne, accessed March 2009. http://susy2.sifolkesundhed.dk/susy.aspx#. 2009b. Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Archives of General Psychiatry 2007;64:1123e31. Thornicroft G, Brohan E, Rose D, Sartorius N, Leese M. Global pattern of experienced and anticipated discrimination against people with schizophrenia: a crosssectional survey. Lancet 2009;373:408e15. Tiihonen J, Lonnqvist J, Wahlbeck K, Klaukka T, Niskanen L, Tanskanen A, et al. 11-year follow-up of mortality in patients with schizophrenia: a populationbased cohort study (FIN11 study). Lancet 2009;374:620e7. World Health Organization. Klassifikation af sygdomme; Udvidet dansk-latinsk udgave af verdenssundhedsorganisationens internationale klassifikation af sygdomme. 8 revision, 1965 [Classification of diseases: Extended Danish-Latin version of the World Health Organization International Classification of Diseases, 8th revision, 1965]. 1st edn. Copenhagen: Danish National Board of Health; 1971. World Health Organization. WHO ICD-10: Psykiske lidelser og adfærdsmæssige forstyrrelser. klassifikation og diagnosekriterier [WHO ICD-10: Mental and Behavioural Disorders. Classification and Diagnostic Criteria]. Copenhagen: Munksgaard Danmark; 1994.
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Heart disease treatment and mortality in schizophrenia and bipolar disorder e Changes in the danish population between 1994 and 2006 Thomas Munk Laursen a, *, Merete Nordentoft b a b
National Center for Register-Based Research, University of Aarhus, Taasingegade 1, DK-8000 Aarhus C, Denmark Psychiatric Center Copenhagen, Copenhagen University, Faculty of Health Sciences, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 October 2009 Received in revised form 26 April 2010 Accepted 28 April 2010
Persons with schizophrenia and bipolar disorder have much higher heart disease mortality rates than the general population. The objective was to compare the general population with persons with schizophrenia, bipolar disorder or other psychiatric disorders in terms of rates of somatic hospitalization and invasive heart disease procedures, and in terms of heart disease mortality during the period 1994 to 2006. Survival analysis was used to analyze heart disease mortality and somatic care trends in a cohort of all persons residing in Denmark. During the study period, heart disease mortality rose significantly among persons with schizophrenia: compared with the general population, the rise in the mortality rate ratio equalled 1.12 (95% confidence interval (CI) 1.08e1.15) every second year. This was not the case for persons with bipolar disorder [1.02 (0.98e1.05), not significant] or other psychiatric disorders [1.00 (0.99e1.01), not significant]. The entire period saw a lower hospitalization rate and fewer invasive cardiac procedures among persons with schizophrenia than among the general population. The higher mortality (with increasing trends) from heart disease in persons with schizophrenia compared to the rest of the cohort members can be explained partly by low rates of invasive cardiac procedures. However, other reasons, such as antipsychotic-induced weight gain, primary prevention, and difficulty following smoking cessation advice could also be part of the explanation. The results call for a greater focus on improvement in somatic care and lifestyle factors for this group of patients. Ó 2010 Elsevier Ltd. All rights reserved.
Keywords: Schizophrenia Bipolar disorder Heart disease mortality
1. Introduction A review found elevated mortality from natural causes in persons with schizophrenia (standardized mortality ratio (SMR) 1.3) and bipolar affective disorder (SMR ¼ 1.5) (Harris and Barraclough, 1998), which was also found in Nordic register-based studies (Osby et al., 2001, 2000; Joukamaa et al., 2001; Mortensen and Juel, 1993; Laursen et al., 2007). It has been suggested that recent decades have seen a rising tendency in the excess mortality of schizophrenic patients (Saha et al., 2007). Heart disease is considered to be the most common cause of death in Western countries (Laursen, 2006; Hennekens et al., 2005), even if mortality from heart disease in general has declined. This decline has been attributed to improved lifestyle and better medical care (Johnsen et al., 2006; Newcomer and Hennekens, 2007). Patients with schizophrenia and bipolar affective have a higher mortality from cardiac disorders than the general population (Laursen et al., 2007),
* Corresponding author. Tel.: þ45 89426816; fax: þ45 89426813. E-mail address: [email protected] (T.M. Laursen). 0022-3956/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2010.04.027
which has recently been suggested to be attributable, among others, to such patients’ lower frequency of hospitalization for heart disease and lesser exposure to cardiac treatment (Laursen et al., 2009). The aim of the paper was to evaluate the change in heart disease related hospitalizations, invasive heart disease procedures and mortality rates in the Danish population from 1994 to 2006. This was done by comparing patients with schizophrenia, bipolar disorder or other psychiatric disorders with the general population. The main focus was to examine if a divergent development between schizophrenia and the general population was present. 2. Method 2.1. Study population and follow-up All persons residing in Denmark during the period 1994e2006 were identified from The Danish Civil Registration System (Pedersen et al., 2006). Among these, 93.4% have been born in Denmark (2009a). Only persons born in Denmark were selected as cohort members, since psychiatric and somatic illness status before
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arrival to Denmark was unknown. The follow-up began on 1st January 1994 or on the cohort member’s 15th birthday, whichever came last. The follow-up ended on 1st January 2007, at the day of death, the day of first admission with heart disease (when this was the outcome), or the day of emigration, whichever came first. Psychiatric and somatic status was diagnosed using the ICD8 (World Health Organization, 1971) classification system until 31st December 1993, and the ICD10 (World Health Organization, 1994) classification from 1st January 1994. The ICD 9 classification was not used in Denmark. Data on psychiatric hospitalizations of the entire Danish population were drawn from the Danish Central Psychiatric Case Register (Munk-Jorgensen and Mortensen, 1997). Patients with schizophrenia (ICD8: 295(exclusive 295.79), ICD10: F20) and bipolar disorder (ICD8: 296.39, 296.19 ICD10: F30, F31) and a group of the remaining psychiatric diagnoses were indentified. Persons were categorized as having schizophrenia/bipolar disorder or another psychiatric diagnosis from the date of their admission to a psychiatric hospital with such a diagnosis. Patients with a diagnosis of both schizophrenia and bipolar disorder (approximately 8% of the bipolar patients) were categorized as having schizophrenia from the day of first diagnosis of schizophrenia. Data on cardiac hospitalizations of the entire Danish population were drawn from the Danish National Hospital Register (Andersen et al., 1999) which was established in 1977 and which contains information on all Danish somatic inpatient hospital contacts. We used only the primary diagnosis of heart disease and registered only those admissions where persons were hospitalized. The definition of heart disease included the following diagnoses (ICD10: I00eI25, I27, I30eI52, ICD8: 390e429). Invasive procedures were defined as Coronary Artery Bypass Graft (CABG), code ¼ 300.09e302.41, KFNA e KFNF or Percutaneous Transluminal Coronary Angioplasty (PTCA), code ¼ 303.50, 303.54, 303.59, KFNG02, KFNG05. The NOMESCO classification of surgical procedures was used as from 1996 (Andersen et al., 1999). In 1994 and 1995, a national classification system was used (Danish National Board of health, 1988). All Danish citizens have access to public health care free of charge. There are no private psychiatric hospitals treating severe mental disorders, and invasive procedures for cardiovascular disorders are almost only carried out at hospitals managed by the regional health authorities. All persons admitted with a heart disease during the 17-year period preceding the study period, i.e. from 1977 to 1994, were excluded from the analysis of heart disease admissions and invasive procedures. This minimized the mixing of prevalent and incident cases in the follow-up period (1994e2006). After the 17-year “washout” period, we assumed all cases to be incident. Underlying causes of death were identified from the Cause of Death Register (Juel and Helweg-Larsen, 1999). We used the definitions of death by heart disease listed above.
(CIs) were used. Trends were analyzed over two-year intervals, except during the first period 1994e1996, where a three-year interval was used. For example, the period from 1999 to 2000 over 2001e2002 to 2003e2004 spanned two calendar periods, and the expected increase in the relative risk was calculated by raising the trend to the power 2. If three periods have elapsed, the expected increase was calculated by raising the trend to the power 3, and so on. The Aalen-Johansen method (Rosthoj et al., 2004) was used to estimate the absolute risk (probability) of receiving cardiac procedures within one year after the first heart disease admission. 3. Results 3.1. Mortality from heart disease During the study period from 1st January 1994 to 31st December 2006, a total of 4,818,168 (Fig. 1) persons were at risk of heart disease mortality. Among these, heart disease was the primary cause of death in 170,248 (Fig. 1). Among those who died from heart disease, 155,904 had not been hospitalized due to psychiatric disease. A total of 978 had been admitted to a psychiatric hospital with a diagnosis of schizophrenia, 876 with a diagnosis of bipolar disorder, and 12,528 with other psychiatric diagnoses. Among persons with no psychiatric disorder, the 2005e2006 rates of mortality from heart disease had dropped to approximately half (for both men and women) the level observed for the
2.2. Statistical analyses Incidence rates of heart disease mortality, heart disease admissions, and invasive procedure were analyzed using Poisson regression with the GENMOD procedure in SAS version 9.1 (SAS Institute Inc, Cary, NC). This method approximates a Cox regression (Andersen et al., 1993; Laird and Olivier, 1981). Outcome measures were denoted as mortality rate ratios (MRR), where death was the end-point of interest; and incidence rate ratios (IRR), where first heart disease admission or first invasive procedure within one year was the end-point. All IRRs or MRRs were adjusted for or stratified by gender, calendar time, and age. IRR and MRR were calculated by log-likelihood estimation, and Wald’s 95% confidence intervals
Fig. 1. Flowchart of number of persons under risk in the follow-up period (1994e2006) and number of cases. Number in bold are referred to in the text in the paper.
T.M. Laursen, M. Nordentoft / Journal of Psychiatric Research 45 (2011) 29e35
1994e1996 period (Table 1). The same trend was seen for persons with other psychiatric disorders than schizophrenia and bipolar disorder. Women with bipolar disorder experienced the same decline, which was also present among men, although to a lesser extent. No decline in heart disease mortality was observed among persons with schizophrenia (Table 1). Compared with persons who had never been admitted to a psychiatric hospital, the heart disease MRRs of individuals admitted to a psychiatric hospital with a diagnosis (including bipolar disorder) other than schizophrenia was approximately 1.5e2 times higher during the entire period, and no increases in tendencies were observed (Fig. 2). Inversely, there was a clear tendency toward an increasing MRR across the entire follow-up period among individual with schizophrenia, with a significantly increasing trend of 1.12 (1.08, 1.15) every second year. In the entire period 1994 to 2006 there was a 76% increase in the excess mortality. Persons with bipolar disorder had confidence intervals that overlapped with “other psychiatric disorders” during the entire period; whereas this was only true for persons with schizophrenia at the start of the follow-up period (Fig. 2). Compared directly with bipolar disorder, schizophrenia showed an increasing trend equalling 1.07 (1.02e1.13) every second year. The results did not differ when stratified according to gender, age (<60, 60e69, 70þ), and time since psychiatric admission (less than 1 year since psychiatric admission, 1e4 years, 5 þ years), and the clear, increasing tendency of MRRs among persons with schizophrenia was found for all age strata. 3.2. Admission with heart disease During follow-up, 340,035 (Fig. 1) persons were admitted to a hospital with a diagnosis of heart disease. Among these 318,207 had never had a psychiatric admission, 1173 had been admitted due to bipolar disorder, and 1283 due to schizophrenia, while 19,372 had been admitted with another psychiatric disorder. The IRRs of heart disease admission in persons with other psychiatric admissions remained at a stable level throughout the follow-up period 25%e30% above that of the reference population of persons never admitted to a psychiatric hospital (Fig. 3). Similarly, no increasing tendency was detected among persons with bipolar disorder. In contrast, among persons with schizophrenia there was a significant 1.07 (1.04e1.10) tendency measured in two-year steps to obtain more heart disease admissions during the follow-up period than
31
among the reference population (Fig. 3). Stratification by gender produced the same pattern in each stratum. Stratification by age also gave the same pattern, but admission IRRs were generally at a lower level among the older cohort members with a psychiatric disorder than among the reference group. 3.3. Invasive heart disease procedures A total of 51,518 (Fig. 1) cohortees had an invasive heart disease procedures performed within one year of their first heart disease admission. Among these, 101 had schizophrenia, 127 bipolar disorder, and 2382 were admitted for other psychiatric disorders. The incidence of first heart disease procedure in the entire cohort rose by 40% (95% CI 40e41%) every second year during the followup period. Compared with the non-psychiatric part of the cohort, no significant trends in the development of invasive procedures were found among the 3 psychiatric disorders (Fig. 4). In the absence of changes in trends over calendar periods, we calculated the average IRR of invasive heart disease procedures for the entire follow-up period: cohort members with schizophrenia had an average IRR of 0.38 (0.31e0.46), while patients with bipolar disorder had an IRR of 0.63 (0.53e0.75) and patients with other psychiatric disorders an IRR of 0.70 (0.67e0.73), results not shown in Table or Figure. Among cohort members with schizophrenia, the probability of being subjected to invasive heart disease procedures rose from 2.8% in the first half of the follow-up (1994e1999) to 11.0% in the second half (2000e2006). The probability rose from 4.1% to 15.8% in cohortees with bipolar disorder and from 5.4% to 18.1% in persons with other psychiatric disorders, and no psychiatric admissions from 7.3% to 22.7% (results not shown in Table or Figure). 4. Discussion 4.1. Key findings During the period 1994e2006, heart disease mortality declined both in the population without psychiatric admissions and among persons with bipolar disorder and other psychiatric admissions; but these two groups had a higher mortality than the general population. In contrast, persons with schizophrenia had high and
Table 1 Number of heart disease deaths and mortality rates per 1000 person years at risk, stratified by psychiatric status. Adjusted for age, with age ¼ 65 as the reference group. Schizophrenia a
Mortality
Year
N
Women 94e96d 97e98 99e00 01e02 03e04 05e06
109 68 69 76 67 66
4.16 3.94 3.98 4.30 3.90 3.85
Men 94e96d 97e98 99e00 01e02 03e04 05e06
112 66 81 74 97 112
11.20 10.06 12.14 10.72 13.62 12.59
a
b
(3.39, (3.06, (3.10, (3.39, (3.03, (2.98,
5.10) 5.06) 5.11) 5.47) 5.02) 4.96)
(9.24, 13.58) (7.86, 12.87) (9.70, 15.19) (8.49, 13.54) (11.09, 16.73) (10.21, 15.53)
Bipolar disorderc
Other psych. adm.
No psych. adm.
Na
Mortalityb
Na
Na
Mortalityb
131 86 85 88 64 71
4.57 3.72 3.35 3.28 2.37 2.51
(3.78, (2.96, (2.67, (2.62, (1.83, (1.96,
5.53) 4.66) 4.21) 4.11) 3.07) 3.2)
1782 1134 1050 1124 936 863
3.70 3.27 2.84 2.91 2.35 2.11
(3.37, (2.96, (2.57, (2.63, (2.12, (1.90,
4.06) 3.62) 3.15) 3.21) 2.61) 2.35)
20,638 12,128 12,155 11,545 10,262 8914
2.15 1.85 1.82 1.70 1.50 1.28
(1.97, (1.70, (1.67, (1.56, (1.38, (1.17,
2.33) 2.01) 1.98) 1.85) 1.63) 1.39)
78 55 38 57 69 54
9.51 9.33 6.01 8.40 9.67 7.21
(7.58, (7.12, (4.36, (6.44, (7.59, (5.50,
11.95) 12.21) 8.30) 10.94) 12.31) 9.46)
1392 889 914 869 872 703
10.45 9.42 9.02 8.14 7.93 6.10
(9.70, (8.66, (8.30, (7.48, (7.29, (5.57,
11.25) 10.24) 9.80) 8.85) 8.63) 6.68)
22,712 13,360 12,459 11,919 10,517 9295
5.82 5.07 4.65 4.35 3.76 3.23
(5.51, (4.79, (4.40, (4.12, (3.55, (3.05,
6.14) 5.35) 4.91) 4.60) 3.97) 3.41)
Mortalityb
N ¼ number of heart disease deaths. Mortality rate per 1000 person years, adjusted for age with the reference group ¼ 65 years old. Thus, the mortality rates can be interpreted as the mortality rate for a 65-year-old person. c Approximately 8% of bipolar patients also had a diagnosis of schizophrenia, and they were categorized as having a schizophrenia diagnosis. d Note: 3-year group. b
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Fig. 2. Mortality rate ratio (MRR) of heart disease mortality among persons with schizophrenia, bipolar disorder, and other psychiatric disorders, compared with persons with no psychiatric admissions (reference group). Men and women combined. MRR, adjusted for age and gender. Vertical lines represent 95% confidence limits (CI). Non-overlapping CI indicates significant different MRR. Test for trends, measured in 2-year steps: Schizophrenia: 1.12 (1.08, 1.15) p < 0.0001; Bipolar disorder: 1.02 (0.98, 1.05) p ¼ 0.40; Other psych. adm.: 1.00 (0.99, 1.01) p ¼ 0.52; Never admitted: Reference.
stable rates of heart disease mortality throughout the entire period, causing the mortality gap between this group and the other groups to widen. Though their mortality remained stable, persons with schizophrenia had slightly higher and increasing rates of admission for heart diseases than the other groups. The rates of invasive heart disease procedures were lower among persons with bipolar disorder than among the general population, and particularly low among persons with schizophrenia throughout the entire period.
4.2. Why is there a mortality gap? Unhealthy lifestyle (Brown et al., 1999), increased smoking (Itkin et al., 2001; Dalack et al., 1998; Goff et al., 2005), and antipsychoticinduced weight gain(Allison et al., 1999; Daumit et al., 2008) in persons with schizophrenia have been established as probable reasons for excess mortality, although a recent study from Finland showed that the use of antipsychotic drugs was associated with lower mortality (Tiihonen et al., 2009).
Fig. 3. Incidence rate ratio (IRR) of heart disease admission among persons with schizophrenia, bipolar disorder, and other psychiatric disorders, compared with persons with no psychiatric admissions (reference group). Men and women combined. IRR, adjusted for age and gender. Vertical lines represent 95% confidence limits (CI). Non-overlapping CI indicates significant different MRR. Test for trends, measured in 2-year steps: Schizophrenia: 1.07 (1.04, 1.10) p < 0.0001; Bipolar disorder: 1.02 (0.99, 1.05) p ¼ 0.29; Other psych. adm.: 1.00 (1.00, 1.01) p ¼ 0.45; Never admitted: Reference.
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33
Fig. 4. Incidence rate ratio (IRR) of invasive heart disease procedure within one year after first heart disease admission among persons with schizophrenia, bipolar disorder, and other psychiatric disorders, compared with persons with no psychiatric admissions (reference group). Men and women combined. IRR, adjusted for age and gender. Vertical lines represent 95% confidence limits (CI). Non-overlapping CI indicates significant different MRR. Note: 1994e96 and 1997e98 is collapsed into one group because of few cases. Test for trends, measured in 2-year steps (except first 5 years): Schizophrenia: 1.03 (0.91, 1.17) p ¼ 0.65; Bipolar disorder: 1.04 (0.94, 1.16) p ¼ 0.43; Other psych. adm.: 1.00 (0.97, 1.02) p ¼ 0.73; Never admitted: Reference.
Physical health is poorer among persons with psychiatric disorders than among the general population. This also contributes to excess mortality in general and mortality from heart disease in particular (Kemp et al., 2009). In a study using Danish data (Laursen et al., 2009) similar to the data used in this study, less somatic hospitalization than needed and less use of invasive heart disease procedures among persons with severe mental disorder (schizophrenia, schizoaffective disorder, and bipolar disorder) than among the general population were suggested as additional reasons for their excess mortality. The same conclusion was reached in a study using Australian data (Lawrence and Coghlan, 2002), where rates of invasive heart disease procedures were also found to be lower in persons with mental disorders. A Finnish study (Rasanen et al., 2007), however, found no support for the theory of under-treatment of somatic diseases in patients with schizophrenia. A low socio-economic status has been associated with a negative impact on rates of death by heart disease (Pocock et al., 1987), and since persons with schizophrenia tend to have lower socioeconomic status (Byrne et al., 2004), some of the excess mortality could thus stem from this association. A mortality gap is present, and the literature suggests that the gap can be at least partly explained by known factors. However, our study also suggests that health inequalities have become even greater during the past decade among persons with schizophrenia. 4.3. Why has the mortality gap expanded? The mortality rate from heart disease remained at a high, stable level throughout the follow-up period in persons with schizophrenia. In contrast, it decreased in all the other sub-populations examined. This indicates that persons with schizophrenia are a particularly vulnerable group of patients, and that active measures should be established to ensure that they will also benefit from the general decline in heart disease mortality. Persons with schizophrenia often encounter discrimination in many areas of their lives (Thornicroft et al., 2009), and insufficient somatic care, as
measured in this paper, seems to be yet another barrier to be overcome. We hypothesize that the mortality gap has widened because patients with schizophrenia have not benefitted from recent therapeutic advances in cardiac therapy to the same extent as the general population which implies a comparative under-treatment of this group of vulnerable patients. The lack of the use of invasive procedures over a period of time will slowly become more and more visible in the cardiac death rates. The present analysis of our data does not allow us to determine whether the current under-treatment is due to patient or doctor behavior or both. It might be that patients were not thoroughly examined, or not referred to relevant treatment. Another possibility is that patients were non-compliant when somatic treatment was offered. However, both patient and doctor behavior can be addressed with flexible, need-based intervention. Our data indicate that this kind of care should be developed to decrease the mortality gap. The widening gap observed in the present study may also be rooted in factors that could not be examined in this study: In the general population, smoking cessation campaigns and smoking area restrictions have positively influenced smoking habits. Smoking decreased from 44% daily smokers in 1987e29% daily smokers in 2005 (2009b). We do not know these figures for patients with schizophrenia in Denmark, but one study has shown excess rates of smoking among persons with schizophrenia (Goff et al., 2005). One explanation for these excess rates could be that these patients found it more difficult to follow smoking cessation advice and to adopt more healthy lifestyle habits regarding diet and exercise than the general population. Finally, the study period saw the introduction of a range of antipsychotic drugs, primarily used in cases of schizophrenia, that have the metabolic syndrome as a possible side effect; it is possible that the introduction of these drugs has caused cardiac mortality to rise (Newcomer, 2007), thereby counteracting the generally positive development in heart disease mortality.
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The mortality rate is a marker of the general health status among persons with schizophrenia, and the lack of improvement in heart disease mortality underlines the need for more somatic care resources for this patient group. A non-optimal lifestyle with respect to avoiding health problems often leads to excess heart disease mortality; thus, a greater focus on lifestyle and help for persons with schizophrenia to successfully follow smoking cessation campaigns and specific programs encouraging their physical activity could probably help lower their excess mortality. Such general campaigns may have to be tailored to the specific needs of this particular patient group. This study shows that whichever initiatives are taken to help narrow the mortality gap in relation to the general population, efforts are needed to raise the level of somatic care e represented here by rates of somatic admission and invasive cardiac procedure e among patients with psychiatric diseases in general, and among persons with schizophrenia in particular. 4.4. Limitations Danish psychiatric care has become more outpatient-based during the past decades. Persons admitted to a psychiatric hospital may therefore be assumed to constitute an ever more selected fraction of psychiatric patients with particularly severe symptoms. To test this assumption, we also analyzed heart disease mortality, admissions, and invasive procedures in a set-up where we included psychiatric outpatients. Information on psychiatric outpatient contacts is only available as from 1995. When we included psychiatric outpatients, we found approximately 11% more persons with schizophrenia who died of a heart disease and 28% more cases with bipolar disorder; however, relative risks and invasive rates were almost identical to the numbers in Figs. 2e4, which suggests that this did not explain the results. We only had information on psychiatric admission from 1970 onwards. Thus, some of the older cohort members could have had a psychiatric admission before 1970 and no psychiatric admissions in the period 1970 to 2006. These persons would not be included in the group of persons with a psychiatric disorder. Persons with a more severe mental disorder have a greater probability of being readmitted; thus, a selection toward more severely ill persons among older cohort members could be expected. However, when we stratified for time since psychiatric admission, we found the same pattern, suggesting that this possible selection did not influence our results. 5. Conclusions The mortality rate from heart disease among persons with schizophrenia remained at a high, stable level throughout the follow-up period. In contrast, mortality rates decreased in the rest of the population. We found no improvement in the low levels of cardiac procedure among persons with schizophrenia during the follow-up period. This constant, low level could be a reason for the comparatively increased level of cardiac death among persons with schizophrenia. However, persons with schizophrenia could also have more difficulty following advice regarding lifestyle improvements, which typically results in higher heart disease mortality. Moreover, the introduction of a range of antipsychotic drugs, primarily for schizophrenia, with metabolic syndrome as a possible side effect during the time period examined may also have contributed to the lack of improvement in mortality. The mortality gap widened, probably due to a combination of the above-mentioned factors. This calls for a greater focus on improvement in somatic care and lifestyle factors for this group of
patients as it is hardly acceptable that persons with schizophrenia should not benefit from the general decrease in heart disease mortality. Role of funding source This study was supported by The Stanley Medical Research Institute. They had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Contributors Authors TML and MN designed the study and wrote the protocol. Author TML and MN managed the literature searches and analyses. Authors TML undertook the statistical analysis and had full access to all of the data in the study. Author TML takes responsibility for the integrity of the data and the accuracy of the data analyses. Author TML wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript. Declaration of interest None. Acknowledgments This study was supported by The Stanley Medical Research Institute. References Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. American Journal of Psychiatry 1999;156:1686e96. Andersen PK, Borgen Ø, Gill RD, Keiding N. Statistical models based on counting processes. Springer-Verlag; 1993. Andersen TF, Madsen M, Jorgensen J, Mellemkjoer L, Olsen JH. The danish national hospital register. A valuable source of data for modern health sciences. Danish Medical Bulletin 1999;46:263e8. Brown S, Birtwistle J, Roe L, Thompson C. The unhealthy lifestyle of people with schizophrenia. Psychological Medicine 1999;29:697e701. Byrne M, Agerbo E, Eaton WW, Mortensen PB. Parental socio-economic status and risk of first admission with schizophrenia- a Danish national register based study. Social Psychiatry and Psychiatric Epidemiology 2004;39:87e96. Dalack GW, Healy DJ, Meador-Woodruff JH. Nicotine dependence in schizophrenia: clinical phenomena and laboratory findings. American Journal of Psychiatry 1998;155:1490e501. Danish National Board of health, 1988. Classification of Surgical Procedure and Therapies Copenhagen. Daumit GL, Goff DC, Meyer JM, Davis VG, Nasrallah HA, McEvoy JP, et al. Antipsychotic effects on estimated 10-year coronary heart disease risk in the CATIE schizophrenia study. Schizophrenia Research 2008;105:175e87. Goff DC, Sullivan LM, McEvoy JP, Meyer JM, Nasrallah HA, Daumit GL, et al. A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls. Schizophrenia Research 2005;80:45e53. Harris EC, Barraclough B. Excess mortality of mental disorder. British Journal of Psychiatry 1998;173:11e53. Hennekens CH, Hennekens AR, Hollar D, Casey DE. Schizophrenia and increased risks of cardiovascular disease. American Heart Journal 2005;150:1115e21. Itkin O, Nemets B, Einat H. Smoking habits in bipolar and schizophrenic outpatients in southern Israel. Journal of Clinical Psychiatry 2001;62:269e72. Johnsen SP, Videbaek J, Pedersen L, Steffensen R, Videbaek R, Niemann T, et al. Survival trends among Danish patients undergoing coronary angiography for known or suspected ischaemic heart disease: a population based follow up study, 1992e2000. Heart 2006;92:27e31. Joukamaa M, Heliovaara M, Knekt P, Aromaa A, Raitasalo R, Lehtinen V. Mental disorders and cause-specific mortality. British Journal of Psychiatry 2001;179:498e502. Juel K, Helweg-Larsen K. The Danish registers of causes of death. Danish Medical Bulletin 1999;46:354e7. Kemp V, Bates A, Isaac M. Behavioural interventions to reduce the risk of physical illness in persons living with mental illness. Current Opinion in Psychiatry 2009;22:194e9.
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