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Excess Mortality in Bipolar and Unipolar Disorder in Sweden
Urban Ösby, MD, PhD;
Lena Brandt, BSc;
Nestor Correia, PhD;
Anders Ekbom, MD, PhD;
Pär Sparén, PhD
Arch Gen Psychiatry. 2001;58:844-850.
ABSTRACT
| |
Background Selected groups of patients with bipolar and unipolar disorder have
an increased mortality rate from suicide and natural causes of death. However,
there has been no population-based study of mortality of patients followed
up from the onset of the illness.
Methods All patients with a hospital diagnosis of bipolar (n = 15 386)
or unipolar (n = 39 182) disorder in Sweden from 1973 to 1995 were identified
from the inpatient register and linked with the national cause-of-death register
to determine the date and cause of death. Overall and cause-specific standardized
mortality ratios (SMRs) and numbers of excess deaths were calculated by 5-year
age classes and 5-year calendar periods.
Results The SMRs for suicide were 15.0 for males and 22.4 for females with bipolar
disorder, and 20.9 and 27.0, respectively, for unipolar disorder. For all
natural causes of death, SMRs were 1.9 for males and 2.1 for females with
bipolar disorder, and 1.5 and 1.6, respectively, for unipolar disorder. For
bipolar disorder, most excess deaths were from natural causes, whereas for
unipolar disorder, most excess deaths were from unnatural causes. The SMR
for suicide was especially high for younger patients during the first years
after the first diagnosis. Increasing SMR for suicide during the period of
study was found for female patients with unipolar disorder.
Conclusions This population-based study of patients treated in the hospital documented
increased SMRs for suicide in patients with bipolar and unipolar disorder.
The SMR for all natural causes of death was also increased, causing about
half the excess deaths.
INTRODUCTION
INCREASED mortality is one of the major adverse effects in individuals
with mood disorders. In bipolar disorder, many studies found a mortality rate
approximately 2 times1, 2, 3, 4, 5, 6, 7, 8
and a suicide mortality rate approximately 10 times that of the general population,
with suicide being the leading single cause of excess mortality. In major
depression, several studies found an increased total mortality,8, 9, 10, 11, 12, 13, 14, 15, 16
with a suicide mortality about 20 times that of the general population.
To obtain accurate risk estimates of the increased mortality among patients
with bipolar and unipolar disorder, large cohorts are needed to identify small
differences in mortality ratios for natural causes of death, which nevertheless
may represent large numbers of excess deaths. Patients need to be followed
up from their first diagnosis, since suicide mortality is especially likely
to be higher in the first phases of the illness and also among younger patients.
Cohorts should be population based to enable inferences to be made from the
findings to large patient groups.
The aim of the present study was to assess mortality, compared with
the general population, in 2 large cohorts comprising all patients in Sweden
with an inpatient diagnosis of bipolar or unipolar disorder. Patients were
identified from the national patient register during 1973 through 1995, and
followed up from the first psychiatric hospital diagnosis. Suicide and other
unnatural causes of death were analyzed as well as cardiovascular death and
other specific natural causes. Standardized mortality ratios (SMRs) and the
numbers of excess deaths were calculated, and the effects of sex, age at first
diagnosis, and duration of follow-up were assessed.
SUBJECTS AND METHODS
SUBJECTS
The Swedish psychiatric inpatient register starts in 1971 and covers
all inpatient treatments since 1973. For each hospitalization, the unique
national registration number, date of admission and discharge, and diagnosis
are registered. No private inpatient facilities exist in Sweden, so the psychiatric
inpatient register is therefore population based. The diagnoses were recorded
according to the International Classification of Diseases,
Eighth Revision (ICD-8), from 1971 to 1986, and according to the International Classification of Diseases, Ninth Revision (ICD-9), from 1987 to 1995. All diagnoses in the register are made by a consultant
in psychiatry at the time of the patient's discharge from the hospital. Several
diagnoses can be recorded at each admission, but only the first (main) diagnosis
was used in this study. To exclude readmitted cases, admissions in the inpatient
register were observed until the end of 1972, and all individuals with a relevant
diagnosis before 1973 were excluded. An upper age limit at the first diagnosis
was set at 70 years. All patients with a first diagnosis of bipolar disorder
or unipolar disorder from January 1, 1973, to December 31, 1995, were identified
in the psychiatric inpatient register. Bipolar disorder was assessed from ICD-8 as manic-depressive psychosis manic type (296.10),
manic-depressive psychosis circular type (296.30), and reactive excitative
psychosis (298.10), and from ICD-9 as unipolar affective
psychosis manic form (296 A), bipolar affective psychosis manic phase (296
C), bipolar affective psychosis mixed form (296 E), and reactive excitative
psychosis (298 B). Unipolar disorder was defined from ICD-8 as melancholic involution psychosis (296.00), manic-depressive psychosis
depressive type (296.20), manic-depressive psychosis alia definita (296.88),
manic-depressive psychosis not otherwise specified (296.99), and reactive
depressive psychosis (298.00), and from ICD-9 as
unipolar affective psychosis melancholic form (296 B), bipolar affective psychosis
melancholic phase (296 D), unspecified affective psychosis (296 X), and reactive
depressive psychosis (298 A).
DEATH REGISTRY
All patients were linked to the national cause-of-death register to
determine the date and cause of death, using the national registration number.
The cause-of-death register is based on the death certificates. Deaths are
classified according to the ICD codes, and on each
certificate there is one underlying cause of death and a possibility to add
contributing causes. For patients who die in the hospital, the death certificate
is made by the consultant in charge, and for deaths out of the hospital, the
physician in charge of the patient certifies the cause of death. When the
cause of death is unclear, an autopsy is performed. In undetermined deaths,
there is always a forensic autopsy. If an autopsy is performed, the death
certificate is considered preliminary until the information from the autopsy
is also included. During 1973-1995, the autopsy frequency for natural causes
of death was 86% in persons aged 15 to 49 years, 68% in persons aged 50 to
69 years, and 45% in persons 70 years and older. For unnatural causes of death,
the autopsy frequency was 90% in persons aged 15 to 49 years, 88% in persons
aged 50 to 69 years, and 53% in persons aged 70 years and older. The cause-of-death
register covers more than 99% of all deaths occurring in Sweden (Statistics
Sweden [federal agency for national statistics], 1998).
DATA ANALYSES
We calculated person-years of follow-up by sex, 5-year age class, and
5-year calendar period, from the date of admission for a first hospitalization
with an eventual bipolar or unipolar disorder diagnosis, occurring from January
1, 1973, until December 31, 1995, or a possible death before this date. Thus,
inpatient periods from the first and later admissions were included in the
person-years count, and deaths could occur both in and out of the hospital.
A bipolar diagnosis was considered more severe than a unipolar diagnosis.
Patients with an initial unipolar diagnosis who were discharged later with
a bipolar diagnosis were, from the date of admission for a hospitalization
with a bipolar diagnosis, excluded from the unipolar group and included among
the bipolar patients. Mortality rates for the Swedish population from 1973
through 1995 retrieved from the cause-of-death register (Statistics Sweden,
1998) were used to estimate the expected number of deaths by 5-year age class
and 5-year calendar periods. The SMRs were calculated as the observed number
of deaths divided by the expected number of deaths, with 95% confidence intervals.17 We calculated the SMRs for each ICD class causes of death and for natural (ICD
classes I-XVI) and unnatural (ICD class XVII; suicide,
accidents, homicide, undetermined) causes, in males and females separately.
The number of excess deaths for natural and unnatural causes was calculated
by subtracting the expected number of deaths from the observed number of deaths.
The SMRs by age at admission and time of follow-up were calculated using
Poisson regression models,18 controlling for
calendar time of the first admission. Age at admission and calendar time were
divided into 5-year intervals, except for the first calendar interval, which
was 3 years. The SMR for suicide was calculated according to age at admission
in the following age groups: younger than 30 years, 30 to 44 years, 45 to
64 years, and 65 years and older; time of follow-up was divided into less
than 1 year, 1 to 3 years, more than 3 years to 5 years, and more than 5 years.
The relative risks for different methods of suicide among patients with bipolar
and unipolar disorder compared with methods of suicide in the general population
in 1973 to 1995 were calculated. Time trends in suicide mortality for the
first 3 years of follow-up were calculated according to 5-year calendar intervals
from 1976 to 1995, for bipolar and unipolar disorder groups.
RESULTS
A total of 6578 males and 8808 females in Sweden with a bipolar disorder
diagnosis during 1973 to 1995 were included in the study (Table 1). For unipolar disorder, a total of 15 829 males and
23 353 females were included. The number of deaths for patients with
a bipolar disorder was 1716 for males and 1747 for females, while there were
4119 male and 4902 female deaths among patients with unipolar disorder. There
was an overlap between the 2 diagnostic groups; 3109 individuals (20% of the
patients with bipolar disorder) were initially discharged with a unipolar
diagnosis. The mean follow-up was about 10 years, irrespective of sex or psychiatric
diagnosis (Table 1).
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Table 1. Number of Cases, Person-years, Age at First Admission, Follow-up,
and Number of Deaths for Patients With Bipolar or Unipolar Disorder Diagnosis
in Sweden, 1973-1995
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The most frequent cause of death was cardiovascular disease, followed
by suicide and cancer in both bipolar and unipolar disorder groups (Table 2). For bipolar disorder, the SMRs
for all deaths were 2.5 in males and 2.7 in females. All natural causes of
death (ICD I-XVI) were increased, except cancer and
diseases of the nervous system for males. For unipolar disorder, SMRs for
all deaths were 2.0 for both sexes. All natural causes of death except cancer
were significantly increased. In patients with bipolar disorder, SMRs for
death from unnatural causes were highest for suicide (15.0 in males and 22.4
in females) and undetermined violent death (10.3 in males and 14.2 in females).
The SMRs for suicide were higher in the unipolar group compared with the bipolar
group, while they tended to be lower for deaths due to undetermined violence.
There were 2130 excess deaths in patients with bipolar disorder and 4585 in
those with unipolar disorder. In the bipolar disorder group, there were more
excess deaths from natural than from unnatural causes, both for males (ratio:
561/470 = 1.19) and for females (ratio: 668/430 = 1.55), while in the unipolar
disorder group, the number of excess deaths was higher from natural causes
for females only (ratio: 1305/1183 = 1.10), but not for males (ratio: 865/1232
= 0.70) (data not shown).
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Table 2. Standardized Mortality Ratios for Patients With Bipolar or
Unipolar Disorder Diagnosis in Sweden, 1973-1995*
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For both bipolar and unipolar disorder, the SMR for all deaths was highest
in patients with their first admission at younger ages (Figure 1). The SMR decreased with increasing age but was still significantly
increased for patients with a first diagnosis at 65 to 69 years of age. An
increased SMR was also most pronounced during the first years of follow-up
after the first diagnosis, with a significant increase still observed after
15 years of follow-up (Figure 2).
There were no sex differences in risk ratios by age at first admission or
time of follow-up.
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Figure 1. Standardized mortality ratios
by age at first admission for patients with bipolar or unipolar disorder in
Sweden during 1973 through 1995, controlling for sex, age at admission, and
calendar period. Shaded area represents 95% confidence interval.
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Figure 2. Standardized mortality ratios
by time of follow-up for patients with bipolar or unipolar disorder in Sweden
during 1973 through 1995, controlling for sex, age at admission, and calendar
period. Shaded area represents 95% confidence interval.
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The SMRs for suicide were elevated for both bipolar and unipolar disorder
in all age classes and follow-up intervals (Table 3). In the bipolar disorder group, SMRs for the younger-than-30-year
age class in the first year of follow-up were 81.6 for males and 71.7 for
females, and SMRs were still 4.7 for males and 13.4 for females in the 65-years-and-older
age class with more than 5 years of follow-up. In all age groups, SMR decreased
with increasing time of follow-up. An interaction between age and duration
of follow-up was observed; the younger the age and shorter the follow-up,
the higher the SMR. However, formal tests for multiplicative interaction effects
did not render significant results.
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Table 3. Standardized Mortality Ratios (SMRs) for Suicide by Age at
First Admission and Duration of Follow-up for Patients With Bipolar or Unipolar
Disorder Diagnosis in Sweden, 1973-1995
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Compared with the general population, jumping as a method of suicide
was more common in patients with bipolar disorder, whereas shooting was less
common for male patients and poisoning less common for female patients (Table 4). Hanging and drowning were more
common as methods of suicide for male patients with unipolar disorder than
in the general population, while shooting was less common. Poisoning was less
common in both male and female patients with unipolar disorder.
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Table 4. Relative Risks for Different Methods of Suicide for Patients
With Bipolar or Unipolar Disorder Diagnosis in Sweden, 1973-1995*
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An increasing time trend in suicide mortality during the first 3 years
of follow-up was found for females with unipolar disorder (P<.001), but not for males or for those with bipolar disorder (Table 5).
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Table 5. Time Trends for Suicide During the First 3 Years of Follow-up
for Patients With Bipolar or Unipolar Disorder Diagnosis in Sweden, 1976-1995*
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COMMENT
The main finding of this study was an increased suicide mortality rate
in patients with bipolar and unipolar disorder, which was most pronounced
at younger ages and in the first years after the initial diagnosis. In patients
with unipolar disorder, suicide mortality for female patients even increased
during the study period. The number of excess deaths from natural causes was
very high, indicating the somatic health of the patients as an important area
for improved treatment besides suicide prevention.
Validation of the clinical diagnosis is a problem with register-based
studies. The diagnostic system changed in Sweden from ICD-8 to ICD-9 in 1987, with accompanying changes
in the diagnostic criteria for bipolar and unipolar disorders. It is likely
that the patients with bipolar disorder in this study had a history of manic
states, since those diagnostic subclassifications were used to define the
bipolar group. The psychotic depressive subclassifications used to define
the unipolar group may also include some patients with bipolar disorder only
diagnosed in a depressive state. Thus, the bipolar group is more strictly
defined than the unipolar group.8 Of the bipolar
patients in our study, 20% had a previous diagnosis of unipolar disorder.
This may lead to an underestimation of suicide mortality for bipolar disorder,
since some patients with bipolar disorder who were initially classified as
having unipolar disorder will die before they get the correct diagnosis. No
validation has been made in Sweden of the clinical affective psychosis diagnoses,
but a validation based on medical records of clinical schizophrenia diagnosis
in Stockholm County, comprising approximately 20% of the Swedish population,
estimated that 80% to 85% of patients with clinical schizophrenia diagnosis
met DSM-III criteria for schizophrenia.19
Another problem with this study is that only patients with a hospital admission
are included, which leads to a selection of severely ill patients, especially
in unipolar disorder, where patients with the less severe forms are expected
to have been in outpatient treatment only. Thus, the mortality ratios found
in this study for unipolar disorder may be exaggerated by a selection of more
severely ill patients, who may have higher mortality rates than patients with
unipolar disorder in general.
In the patients with bipolar disorder, suicide mortality was lower and
mortality from natural causes was higher than in the patients with unipolar
disorder, which is in line with earlier findings.5, 8
When suicide mortality in our bipolar group was compared with the aggregate
mortality ratios of a meta-analysis of mortality studies in psychiatric disorders,20 our rates were several times higher (male-female:
15.05/22.37 vs 5.71/5.88). Only one previous study of mortality in mood disorder
has used national population-based patient data, followed up from the first
diagnosis,8 and the reported suicide mortality
from that study was in accordance with our findings. Since mortality in suicide
is particularly increased in the first years after the first admission and
will tend to decline with time of follow-up, first-episode cohort studies
provide better estimates of the excess suicide mortality than studies based
on cases identified later during the course of the illness. Suicide mortality
in our patients with unipolar disorder, however, was not different from that
reported in the meta-analysis (male-female: 20.93/26.98 vs 15.73/27.81). The
increased mortality rate in undetermined death in both bipolar and unipolar
disorder groups is to a large extent likely to be due to suicides.21, 22 In our study, an increase in SMR
in suicide during the period of study was apparent among female patients with
unipolar disorder. There are other previous findings of increasing time trends
in suicide mortality in mood disorders8 and
also in schizophrenia.23, 24 In
the Swedish population, suicide as a cause of death has decreased during the
past decades, hypothesized to be an effect of increased use of antidepressant
drugs.25 The finding of increasing SMR for
suicide indicates that the outcome among patients with unipolar disorder has
not improved, although a selection of more severely ill patients with higher
suicide risks as inpatients over time cannot be excluded. The proportion of
violent methods of suicide such as jumping (bipolar disorder) and hanging
and drowning (unipolar disorder) were higher, while the use of poisoning was
lower in patients with unipolar disorder. Shooting as a method of suicide
was lower for male patients with bipolar and unipolar disorder, which may
reflect a reduced access to guns, possibly indicating that the efforts of
society and the psychiatric services to reduce access to guns have been successful.
A similar result was found for patients with schizophrenia.26
There are several studies suggesting that patients with bipolar disorder
selected for and compliant with long-term treatment at specialized lithium
clinics have lower-than-expected mortality from suicide.27, 28, 29, 30, 31, 32
Unfortunately, there is no information about treatment in the patient registry.
However, before such programs are initiated for all patients, one should keep
in mind that patients in special lithium programs constitute a selected group,
who are probably more compliant compared with other patients with such disorders.
Thus, more studies are needed in population-based samples to assess the impact
of such measures on the risk of suicide.
Considering natural causes of death, the increased mortality for cardiovascular
and respiratory disease found in both bipolar and unipolar disorder patients
is in accordance with the findings of other studies.7, 20, 33
One possible explanation is higher smoking rates among this population, which
also may be the explanation for the increased mortality due to cerebrovascular
disease. However, there are also studies that did not find an increased mortality
rate from cardiovascular disease,12 notably
studies of patients receiving long-term lithium treatment. Whether this difference
is an effect of the specific treatment or the selection of patients is not
yet clear. In unipolar disorder, there are findings of an increased risk for
coronary heart disease in both men and women.34, 35, 36
Depression must be considered as a risk factor for coronary heart disease,
although the mechanism is not known. It may be a direct effect on heart rate
or increasing platelet aggregation, or an indirect effect by poor self-care
or social isolation.
The number of excess deaths, rather than increased relative mortality,
should be the target for preventive programs, since prevention should focus
on the number of saved lives. In bipolar disorder, the total number of excess
deaths was slightly higher for natural than for unnatural causes of death,
while in unipolar disorder the total number of excess deaths was larger for
unnatural causes. Suicide was the specific cause of death that caused most
excess deaths in both bipolar and unipolar disorder groups, but due to the
higher prevalence of unipolar disorder there were approximately 3 times as
many excess deaths from suicide in patients with unipolar disorder. Studies
of suicide risks have found that the strongest risk factor is mental illness
necessitating hospital admission.37, 38, 39
Suicide prevention programs should target patients in the first years after
the first diagnosis, but there is also a need for adequate somatic care and
general health measures to be improved, especially in bipolar disorder.
In conclusion, this study found a markedly increased mortality rate
for patients with bipolar and unipolar disorder. Future studies should focus
on the effects of specific interventions such as lithium therapy and other
specific treatments. Our results also underscore the need to continuously
monitor mortality in those patient groups to improve treatment.
AUTHOR INFORMATION
Accepted for publication April 19, 2001.
This study was supported by grant 1998 7289 from the Stockholm County
Council.
The study was conducted within the Swedish Schizophrenia Sibling Pair
study. We are also indebted to Lars Terenius, MD, PhD, Department of Clinical
Neuroscience, Karolinska Institutet, Stockholm, for useful opinions and critical
revisions of the manuscript.
From the Departments of Clinical Neuroscience (Dr Ösby and Ms
Brandt) and Medical Epidemiology (Drs Ösby, Correia, Ekbom, and Sparén,
and Ms Brandt), Karolinska Institutet, Stockholm, Sweden.
Corresponding author and reprints: Urban Ösby, MD, PhD, Karolinska
sjukhuset S4, S-171 76 Stockholm, Sweden (e-mail: Urban.Osby{at}nvso.sll.se).
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Depression, cardiac mortality and all-cause mortality
Seymour and Benning
Adv. Psychiatr. Treat. 2009;15:107-113.
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Premature Mortality From General Medical Illnesses Among Persons With Bipolar Disorder: A Review
Roshanaei-Moghaddam and Katon
Psychiatr. Serv. 2009;60:147-156.
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Excess mortality, causes of death and prognostic factors in anorexia nervosa
Papadopoulos et al.
Br. J. Psychiatry 2009;194:10-17.
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Risk of suicide after suicide attempt according to coexisting psychiatric disorder: Swedish cohort study with long term follow-up
Tidemalm et al.
BMJ 2008;337:a2205-a2205.
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The Burden of Mental Disorders
Eaton et al.
Epidemiol Rev 2008;30:1-14.
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Metabolic and Cardiovascular Adverse Events Associated With Antipsychotic Treatment in Children and Adolescents
McIntyre and Jerrell
Arch Pediatr Adolesc Med 2008;162:929-935.
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Risk of stroke with typical and atypical anti-psychotics: a retrospective cohort study including unexposed subjects
Sacchetti et al.
J Psychopharmacol 2008;22:39-46.
ABSTRACT
No Higher Risk of Myocardial Infarction Among Bipolar Patients in a 6-Year Follow-Up of Acute Mood Episodes
Lin et al.
Psychosom. Med. 2008;70:73-76.
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Lifetime and 12-Month Prevalence of Bipolar Spectrum Disorder in the National Comorbidity Survey Replication
Merikangas et al.
Arch Gen Psychiatry 2007;64:543-552.
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All-cause mortality among recipients of electroconvulsive therapy: Register-based cohort study
Munk-Olsen et al.
Br. J. Psychiatry 2007;190:435-439.
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The bipolar spectrum
Angst
Br. J. Psychiatry 2007;190:189-191.
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Bipolar Disorder Clinical Synthesis: Where Does the Evidence Lead?
Sachs
Focus 2007;5:3-13.
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Medical Comorbidity in Bipolar Disorder: Implications for Functional Outcomes and Health Service Utilization
McIntyre et al.
Psychiatr. Serv. 2006;57:1140-1144.
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Antidepressant drug therapy and suicide in severely depressed children and adults: a case-control study.
Olfson et al.
Arch Gen Psychiatry 2006;63:865-872.
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Disparities in Diabetes Care: Impact of Mental Illness
Frayne et al.
Arch Intern Med 2005;165:2631-2638.
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Metabolism, lifestyle and bipolar affective disorder
Morriss and Mohammed
J Psychopharmacol 2005;19:94-101.
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Obesity and Psychiatric Disorders: Frequently Encountered Clinical Questions
McIntyre and Konarski
Focus 2005;3:511-519.
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The Increasing Medical Burden in Bipolar Disorder
Kupfer
JAMA 2005;293:2528-2530.
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Prospective study of risk factors for attempted suicide among patients with DSM-IV major depressive disorder
SOKERO et al.
Br. J. Psychiatry 2005;186:314-318.
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Smoking and the Risk of Suicidal Behavior: A Prospective Study of a Community Sample
Breslau et al.
Arch Gen Psychiatry 2005;62:328-334.
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Bipolar I disorder: Psychopathology, medical management and dental implications
FRIEDLANDER et al.
Journal of the American Dental Association 2002;133:1209-1217.
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Other Health Consequences of Depression
JWatch Psychiatry 2001;2001:2-2.
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