Does the risk of developing dementia increase with the
number of episodes in patients with depressive disorder and
in patients with bipolar disorder?
L V Kessing, P K Andersen
See end of article for
L V Kessing, Department of
Hospital of Copenhagen,
Blegdamsvej 9, DK 2100
Copenhagen Ø, Denmark;
In revised form
23 February 2004
Accepted 6 March 2004
J Neurol Neurosurg Psychiatry 2004;75:1662–1666. doi: 10.1136/jnnp.2003.031773
Objective: Several findings suggest that some patients with depressive or bipolar disorder may be at
increased risk of developing dementia. The present study aimed to investigate whether the risk of
developing dementia increases with the number of affective episodes in patients with depressive disorder
and in patients with bipolar disorder.
Methods: This was a case register study including all hospital admissions with primary affective disorder in
Denmark during 1970–99. The effect of the number of prior episodes leading to admission on the rate of
readmission with a diagnosis of dementia following the first discharge after 1985 was estimated. A total of
18 726 patients with depressive disorder and 4248 patients with bipolar disorder were included in the
Results: The rate of a diagnosis of dementia on readmission was significantly related to the number of
prior affective episodes leading to admission. On average, the rate of dementia tended to increase 13%
with every episode leading to admission for patients with depressive disorder and 6% with every episode
leading to admission for patients with bipolar disorder, when adjusted for differences in age and sex.
Conclusion: On average, the risk of dementia seems to increase with the number of episodes in depressive
and bipolar affective disorders.
reviews see references 1, 2). Thus, several prospective
community studies suggest that depressive symptoms or
depression at baseline are associated with increased risk
of developing cognitive decline at follow up3–10although
other studies have failed to confirm these findings.11–13
Additionally, some retrospective studies of patients with
Alzheimer’s disease suggest that a history of depression may
be associated with increased risk of developing late onset
Alzheimer’s disease3 14–16and some uncontrolled follow up
studies of patients with depression suggest that subgroups of
patients with depression are at increased risk of developing
dementia.17–21Finally, in two controlled (historical), prospec-
tive long term studies of patients with affective disorder we
found that patients previously discharged from psychiatric
hospitals with a diagnosis of single or recurrent depression or
with bipolar disorder had increased risk of getting a diagnosis
of dementia on readmission compared with patients with a
diagnosis of neurosis and compared with the general
population22or patients with a diagnosis of osteoarthritis or
The more precise nature of such a putative association
between depression and dementia, however, has seldom been
studied. Very few studies have investigated how the course of
illness of affective disorder may affect the risk of developing
cognitive decline or dementia. In one study, the number of
depressive episodes was found to be associated with the
severity of cognitive impairment,5and conversely in another
study, persistent but not episodic depressive episodes were
found to be associated with cognitive decline.10Additionally,
a few cross-sectional studies of patients who were investi-
gated in the euthymic phase of affective disorder found that
the number of prior affective episodes was associated with
the severity of cognitive dysfunction24–27but other studies
have not confirmed this finding.28
depression or depressive symptoms may be a risk factor
for development of cognitive decline or dementia (for
Although the literature is sparse, we hypothesised that the
number of prior affective episodes (depressive or manic) is
associated with increased risk of developing dementia. The aim
of the present study was to investigate whether the number of
prior admissions for patients hospitalised with depressive or
bipolar disorder predicted increasedriskof subsequently getting
readmitted with a diagnosis of dementia using a national case
register of all admissions to psychiatric wards.
Only patients who had been hospitalised at least once on a
psychiatric ward and only affective episodes leading to
admission were included in the study; these patients thus
represent the more severely influenced proportion of patients.
Data on treatment or outpatient status were not available.
In Denmark, all psychiatric admissions have been registered
in a nationwide register for the 5.1 million inhabitants.29All
inhabitants of Denmark have a unique person identification
number that can be logically checked for errors, so it can be
established with great certainty if a patient has been
admitted previously, irrespective of changes in name etc.
Censoring due to death and causes of death can also be
established with equal certainty as the same identification
number is used across all public registration systems.
International Classification of Diseases (ICD), 8th revision30
was used in Denmark. For various reasons, and to achieve
better diagnostic reliability over time, it was decided not to
change to the ICD, 9th revision in 1978. Since 1 January 1994
the ICD-1031has been used.
Patients who had had their first ever discharge in the period
between 1 April 1970 and 31 December 1999 were identified
Abbreviation: ICD, International Classification of Diseases
from the register. Patients were included in the study at the
time of first discharge from a psychiatric hospital after
1 January 1986 provided that they, at their first ever
discharge after 1 April 1970, had got a diagnosis of affective
disorder and provided that their main diagnosis was not of
organic psychosis (ICD-8 codes, 290–294 and ICD-10, code
DF00-09) or schizophrenia (ICD-8, code 295 and ICD-10,
code DF20-29) at other discharges before 1 January 1986. A
diagnosis of affective disorder included depressive episode/
recurrent depression (ICD-8, codes 296.09 and 296.29, and
ICD-10, code DF32-33.9) and manic, mixed episode/bipolar
disorder (ICD-8, codes 296.19 and 296.39, and ICD-10, codes
DF30-31.9 and DF38.00). Patients were classified as having
bipolar disorder if they had had a diagnosis of manic, mixed
episode/bipolar disorder before their date of entry into the
study and as having depressive disorder if they had not had a
diagnosis of manic, mixed episode/bipolar disorder. Patients
were also classified according to their number of affective
episodes in the period between 1 April 1970 and their entry
into the study.
The hazard ratio (HR) of the number of episodes leading to
admission on the rate of readmission with a discharge
diagnosis of dementia was estimated using a Cox propor-
tional hazards regression model. Time to dementia was
censored if patients died, emigrated, or were not diagnosed as
having dementia on readmission before 31 December 1999.
The hazard ratio was adjusted for differences in sex, age, and
calendar time at the first discharge date following 1985. The
likelihood ratio test was used to assess whether the number
of episodes leading to admission could be included as an
ordinal variable and to compare the effect of episodes leading
to admission for patients with depressive disorder and
patients with bipolar disorder.
The model assumptions of proportional hazards between
depressive and bipolar patients with different number of
episodes leading to admission were checked graphically using
log-log survival plots, and numerically by entering appro-
priate time dependent covariates.
During the study period from 1970 to 1999, 40 106 patients
were diagnosed with a manic-depressive psychosis (ICD-8) or
affective disorder (ICD-10) at first discharge. Among these
patients, the study population was defined as the 18 726
patients with depressive disorder and 4248 patients with
bipolar disorder who were admitted at least once between
1986 and 1999. Following entry into the study, 337 (1.8%) of
the patients with depressive disorder and 97 (2.3%) of the
patients with bipolar disorder got a diagnosis of dementia at
discharge from a subsequent readmission. Further character-
istics of the patients included are presented in table 1.
The results of the Cox regression analysis of the effect of
the number of prior affective episodes leading to admission,
adjusted for the effect of age, sex, and calendar time, are
presented in table 2. Data were missing for 186 patients
(0.8%) of the total sample of 22 974 patients leaving 22 788
patients for the analyses. In the model, no significant effect
of sex was found (HR 1.09, 95% CI 0.89 to 1.35) but the rate
of dementia increased with age (HR 1.06, 95% CI 1.048 to
1.064)—that is, a 6% increase with every year. Patients with
one manic episode (n=2187) had a 1.46 (95% CI 1.01 to
2.13) times increased rate of dementia compared with
patients with one depressive episode (n=15 085).
First, the number of episodes was included as a categorical
variable separately for patients with depressive disorder and
patients with bipolar disorder. Patients with one episode
were chosen as the reference group. The hazard ratios
presented thus indicate the rate of dementia for patients
with a given number of prior episodes leading to admission
compared with the rate for patients with one episode.
Patients with two prior depressive episodes leading to
admission had the same rate of dementia (HR 1.00, 95% CI
0.25 to 4.06) as patients with one prior episode. Patients with
three prior depressive episodes had a 2.89 times increased
rate of dementia (95% CI 0.64 to 13.02) compared with
patients with one prior depressive episode, etc. For bipolar
patients, patients with two manic episodes and patients with
three manic episodes did not have increased rate of dementia
compared with patients with one depressive episode, whereas
patients with four or more episodes had increased rate of
dementia. The rate of dementia varied significantly with the
number of episodes for patients with depressive disorder
(x2=27.0, df=4; p,0.001) and for patients with bipolar
disorder (x2=31.9, df=4; p,0.001). The difference between
the effects of episodes in depressive disorder and bipolar
disorder was significant according to a likelihood ratio test
assumption was found to be reasonably fulfilled.
Secondly, the number of episodes leading to admission was
included as an ordinal variable. In this model, the hazard
ratios indicate the factor change in the rate of dementia for
each affective episode. Patients with depressive disorder and
patients with bipolar disorder were considered separately.
The episode number significantly predicted the rate of
subsequent dementia: for every new episode leading to
admission the rate increased on average 13% (95% CI 9% to
16%) for patients with depressive disorder and 6% (95% CI
Characteristics of the patients at the index
No. of patients
Female sex (%)
Age in years, (mean (SD))
Proportion with dementia
during follow up (%)*
Proportion dead during
follow up (%)?
*Proportion of patients who had a diagnosis of dementia at readmission
following the index episode.
?Proportion of patients censored because of death after the index
The effect of the number of episodes
Depressive disorderBipolar disorder
(0.25 to 4.06)
(0.64 to 13.02)
(0.58 to 12.58)
(1.39 to 27.22)
(0.05 to 2.56)
(0.15 to 4.43)
(0.39 to 10.68)
(0.69 to 14.75)
(1.01 to 2.13)
3 episodes735 323
4 episodes 459243
>5 episodes983 1 083
*Hazard ratio: the rate of a diagnosis of dementia for patients with a
given number of prior episodes compared with the rate for patients with
one prior episode.
?The effect of the type of disorder for patients with one episode.
All hazard ratios are adjusted for the effects of sex, age, and calendar
Dementia and number of affective episodes1663
3% to 10%) for patients with bipolar disorder. To explore
whether these associations also apply to patients with an
interval of one year or more between the index episode and
dementia, the analysis was repeated including only those
cases in which time under risk was greater than one year.
Similar significant effects were found (depressive disorder:
11% (95% CI: 6% to 17%); bipolar disorder: 8% (95% CI 3% to
13%)). However, a likelihood ratio test suggested that the
number of episodes expressed as an ordinal variable gave an
inferior fit to the data than a categorical variable (x2=17.0,
df=6; p,0.01) and therefore these should be taken as a
rough indication of a general increasing trend.
To explore whether the probability of getting a diagnosis of
dementia simply increased with the number of admissions,
the proportion of patients with a diagnosis of dementia at
each admission was calculated. Among all patients admitted
twice, 10.1% had a diagnosis of dementia at the second
admission. The corresponding proportions were 16.1% for
patients admitted three times and 15.8% for patients
admitted four times. Among patients admitted five times or
more, 9.3% got a diagnosis of dementia at the fifth or at a
later admission. Thus, no systematic association was found
between the number of admissions and the proportion of
patients who were diagnosed as having dementia.
The present study showed that the risk of getting a diagnosis
of dementia at readmission was affected significantly by the
number of prior episodes leading to admission in depressive
disorder and bipolar disorder. The effect of episodes leading
to admission was significantly greater for patients with
depressive disorder than for patients with bipolar disorder.
The rate of dementia increased on average 13% (95 CI 9% to
16%) with every episode leading to admission for patients
with depressive disorder and 6% (95 CI 3% to 10%) with
every episode leading to admission for bipolar patients.
It should be acknowledged that the study only included
patients who had been hospitalised at least once and that
affective episodes were included only if they resulted in
hospitalisation and that the outcome (a diagnosis of
dementia) only related to patients who were readmitted.
The latter is illustrated by the relatively low incidence of
dementia found in the study. Thus, patients may have been
diagnosed as having dementia in places outside psychiatric
and somatic wards following first admission without this
being recorded in the registers used as the source for data for
the present study.
Validity of the diagnoses of affective disorders
The diagnoses in the register are made by different clinicians
throughout Denmark and are not standardised for research
purposes. Diagnostic shifts due to transfer to ICD-9 are
avoided, since ICD-8 was used in Denmark until ICD-10.
The validity of the affective diagnoses has been found to be
good in a validity study of the register.32In a random
subsample of 100 patients from the register with clinical
ICD-8 diagnoses of manic-depressive psychosis at first
admission, 95 patients received a lifetime ICD-10 diagnosis
of affective disorder according to research diagnostic criteria.
Part of the problem with the diagnostic validity is the
diagnostic concordance between ICD-8 and ICD-10. From the
present register, the concordance between the two diagnostic
systems has been found to be as high as 84% for patients with
affective disorder and 87% for patients with dementia.33Thus,
13% of patients who received an ICD-8 diagnosis of dementia
received an ICD-10 diagnosis of another organic mental
disorder or alcohol induced mental disorder (F06-F10).
Misclassification of the diagnosis of dementia
It is well known that depression may be misclassified as
dementia when symptoms of cognitive dysfunction are
prominent—that is, some of the diagnoses of dementia in
the present study in reality represent a pseudodemented
state. However, pseudodementia is in general milder and
more fluctuating in nature, while diagnoses of dementia that
are given on discharge from psychiatric departments follow-
ing admission for days or weeks, presumably describe a
moderate to severe, progressive, demented condition. One
may thus presume that the risk of misclassification is low. To
investigate this further, 30 patients with primary affective
disorder and a subsequent main or auxiliary diagnosis of
dementia were randomly selected from the register (Kessing,
unpublished data). The majority of these patients scored
within the demented range on two different scales of
cognitive assessment (70% of patients scored below 100 on
the CAMCOG (Cambridge Cognitive Examination) rating
scale (range 0–120)34with an average of 89.5 (SD 19.7) and
96.2% of patients scored below 1 on the Global Deterioration
Scale35(range 1–6) with an average of 3.9 (1.0)). One may
argue that patients who eventually got a diagnosis of
dementia might have had several admissions previously at
which dementia might have been misdiagnosed as depres-
sion. This possibility did, however, not explain our results as
additional analyses revealed that the association between the
number of episodes leading to admission and the risk of
dementia was also found among patients with more than one
year between last admission for depression and admission
with a diagnosis of dementia. Anyway, it should be acknowl-
edged that there is a need for validation of the diagnosis of
dementia through criterion based diagnoses made at repeated
assessments over time.
We find no reason to believe that doctors in psychiatric wards
may be more observant of symptoms of dementia in patients
who have been admitted with depression or mania many
times than in patients who have seldom been admitted.
On the other hand, it has previously been found that the
risk of getting readmitted increases with the number of prior
episodes leading to admission for patients with affective
disorders in Denmark.36 37This may by itself increase the
probability for patients with many prior affective episodes of
getting a diagnosis of dementia at admission as these
patients have a greater chance of seeing a doctor in a
psychiatric ward than patients with fewer admissions.
However, arguing against this possibility, it was not found
that the probability of getting a diagnosis of dementia simply
increased with the number of admissions (the proportion of
patients who got a diagnosis of dementia at the fifth or at a
later admission was less than the proportion who got a
diagnosis of dementia at the second, third, or fourth
admission, respectively). Thus, we do not believe that such
putative detection bias explain our finding of an association
between the number of affective episodes and the risk of
It is unlikely that the demonstrated association between
affective disorder and dementia was a result of intracranial
infection, cerebral arteriosclerosis, cerebrovascular accidents
as stroke, haemorrhage, epilepsy, intracranial neoplasm,
degenerative diseases of the central nervous system, brain
trauma, endocrine disorders, metabolic and nutritional
disorders, systemic infections, drug or poison intoxication,
or other physical conditions, since dementia related to these
disorders was coded elsewhere in ICD-8 (code 292.0 – 294.9)
and ICD-10 (code DF00-09). Additionally, patients who,
1664 Kessing, Andersen
following the first discharge, at a subsequent admission
received a discharge diagnosis of brain disorders other than
dementia were censored.
Also, in our previous studies we found that the association
between affective disorder and dementia could not be
explained by alcoholism or other substance abuse.22 23
Although we cannot exclude methodological considerations,
we do not believe that the finding of an increasing risk of
getting a diagnosis of dementia with the number of affective
episodes leading to hospitalisation is simply a result of
With regard to longitudinal studies of depressive disorder,
our findings are in accordance with the finding of an
association between the number of depressive episodes and
the risk of developing Alzheimer’s disease in the follow-up
study by Andersen5but contrast with the finding in the four
year study by Paterniti et al.10It is possible that a follow up
time of four years is too short, as suggested by the studies of
Speck et al3and Palsson et al8depression may act as a
predictor of dementia particularly when there is a large
interval between onset of depression and onset of dementia
(10 years or more between the onset of depression and the
onset of dementia). It is further possible that the association
is more pronounced or is found only in patients with severe
affective disorder for example as reflected by the need of
hospitalisation as in the present study.
No prior longitudinal study of bipolar disorder has
investigated the association between the number of episodes
and the risk of developing dementia.
Data on treatment were not available in the present study. If
treatment should explain the finding of an effect of the
number of affective episodes on the risk of developing
dementia, then this treatment should be given continuously
for long periods of time for both patients with depressive
disorder and patients with bipolar disorder. Antidepressants
are usually only given for shorter periods in patients with
bipolar disorder,38however anxiolytics may often be given to
both patient groups for a longer time. As indicated by Jorm,1
the literature is inconsistent as benzodiazepine use has been
associated with cognitive decline39as well as a lower
incidence of Alzheimer’s disease.40
The study supports the possibility of a direct association
between affective disorder and dementia without any
intermittent cerebral disorder1 2and further supports the
hypothesis that affective episodes may cause permanent
affection of the brain (the scar hypothesis as suggested by
Post and others41). If our results can be confirmed in future
studies they underscore the importance of early and
sustained prophylaxis of the evolving process of the illness
in depressive and bipolar disorders.41The pathophysiology
behind such a direct association is unknown, although the
hypothesis that affective disorder may cause dementia
through a glucocorticoid cascade is gaining interest.42Sub-
diagnoses of dementia were not investigated in the present
study, since it is difficult clinically to distinguish between—
for example, Alzheimer’s disease (code 290.10) and dementia
senilis (code 290.09)—and since, especially early in the
observation period, there was seldom access to single photon
emission computed tomography and magnetic resonance
Our findings need to be replicated in prospective studies
involving large groups of patients followed over many years
with regular assessments of the cognitive function. Further
research, including brain imaging studies, within this field of
affective disorder and dementia may provide further under-
standing of the pathophysiology underlying these disorders.
L V Kessing, Department of Psychiatry, University of Copenhagen,
Rigshospitalet, Copenhagen, Denmark
P K Andersen, Department of Biostatistics, University of Copenhagen
and Department of Psychiatric Demography, University of Aarhus,
Psychiatric Hospital, Risskov, Denmark
This study was supported by the Stanley Medical Research Institute and
Competing interests: none declared
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HISTORICAL NOTE ..........................................................................................
From orthostatic hypotension to Shy-Drager syndrome
accounts for 3% of emergency room visits and 1–6% of all
hospital admissions,1Pierre Adolph Piorry2(1794–1879) in
yncope derives from the Greek synkoptein, meaning to
strike, cut off, or weary. Hippocrates and biblical texts
describe victims of fainting. In the USA syncope
‘‘When a patient faints, symptoms improve when he is laid
Piorry was a pioneer of percussion and pleximetry, best
remembered for his work in chest diseases and for coining
the term ‘‘uraemia’’.
Thomas Addison, when describing postural syncope in
adrenal failure, also noted:
‘‘Attacks of giddiness and dimness of sight…would occur
always when in the standing posture and were instantly
relieved by sitting or lying down.’’
Bradbury and Eggleston4first recorded a recurrent fainting
of unknown cause in 1925 in three patients subject to attacks
of idiopathic orthostatic hypotension. Many lone and familial
cases have subsequently appeared in the literature.5
Orthostatic hypotension in association with other neuro-
logical disease occurs in tabes, syringomyelia, spinal cord
injury, and in polyneuropathies, Parkinsonism, multiple
system atrophy (MSA), and a variety of cerebrovascular
and tumourous lesions. In 1960 Milton Shy at the NIH and
Glen Albert Drager of Houston described comprehensively
the clinicopathology of MSA:
‘‘A neurological syndrome associated with orthostatic
hypotension…which is of adult onset and consists of
orthostatic hypotension, bladder and bowel incontinence,
anhidrosis, iris atrophy, amyotrophy, ataxia, rigidity and
tremor; intellect is unaffected’’6
Schatz later revised7the nosology for autonomic disorders:
(1) primary, autonomic failure (idiopathic orthostatic hypo-
tension or Bradbury-Eggleston syndrome) with no neurologic
defects other than autonomic dysfunction; (2) multiple
system atrophy, equivalent to Shy-Drager syndrome (a
sporadic, progressive, adult onset disorder characterised by
autonomic dysfunction, parkinsonism, and ataxia in any
combination); and (3) secondary autonomic failure deline-
ates diseases in which the cause is known (for example
diabetes, amyloidosis, dopamine beta-hydroxylase deficiency,
and drug side effects).
The American Autonomic Society has defined multiple
system atrophy as:
‘‘A sporadic, progressive, adult onset disorder character-
ized by autonomic dysfunction, Parkinsonism, and
ataxia (a failure of muscular coordination) in any
combination.…The main features are: Parkinsonism,
Cerebellar signs, Autonomic Failure, Striatonigral
Degeneration, Sporadic Olivo-ponto-cerebellar Atrophy,
George Milton Shy (1919–1967) qualified in Oregon in
1943 and after brief war service, in which he was wounded,
studied neurology at the Montreal Neurological Institute, and
at the National Hospital, Queen Square. Unusually for an
American, he became MRCP London by examination, in
1947. He carried out highly regarded research on myopathies
and published extensively. His work on the Kearns-Sayre
syndrome, oculopharyngeal myopathy (Shy-Gonatas syn-
drome), and a myopathy of infants (Shy-Magee syndrome)
are lasting monuments to his protean interests. In 1953 he
Neurological Diseases and Blindness, Bethesda, and in 1962
chairman of neurology in Pennsylvania, before taking the
chair and directorship of the New York Neurological
Institute, Columbia in 1967. Aged only 47 he died suddenly
a few weeks later.
Little is recorded about Drager (1917–1967), a talented
physician at Baylor College of Medicine, Houston, who also
died young, in the same year as Shy.
the National Institute of
J M S Pearce
304 Beverley Road, Anlaby, East Yorkshire HU10 7BG, UK;
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1666 Kessing, Andersen