REVIEW

CURRENT
OPINION Depression and the risk for dementia
Lars Vedel Kessing

Purpose of review
Depression is associated with increased risk of subsequent development of dementia; however, the nature
of the association is still poorly understood. The purpose of the review was based on recent studies to
discuss whether depression is a prodromal state of dementia or an independent risk factor for dementia, as
well as to discuss how the type of depression, the type of dementia, and antidepressant treatment influence
the association.
Recent findings
Findings from recent studies suggest that some forms of depressive illness, for example early-onset
depression before age 65 years and recurrent depression, may constitute long-term risk factors for
development of dementia, whereas the onset of more recent depressive symptoms may reflect
a prodromal phase of dementia. It is not clear whether specific subtypes of depression correspond to
specific types of dementia. Recent studies suggest that long-term treatment with antidepressants
may decrease the risk of developing some types of dementia, depending on the type of depressive
disorder.
Summary
This review has shown that the type of depression and dementia, as well as the effect of drug treatment,
has to be considered to improve knowledge on the association between depression and dementia.
Keywords
depression, depressive disorder, recurrent depression, risk of Alzheimer’s disease, risk of dementia, risk of
vascular dementia

INTRODUCTION IS DEPRESSION A PRODROMAL STATE

Depression and dementia may be related in several
ways. Dementia is associated with increased risk of
developing depression, and conversely depression
seems to increase the risk of subsequently develop-
ing dementia. Regarding the latter association, two
separate meta-analyses concluded that depression
increases the risk of developing subsequent demen-
tia two-fold [1,2]. A number of recent studies
& & && & &
(e.g. [3 ,4 ,5 ]) and reviews [6 ,7 ] have confirmed
this association in general. However, the nature of
the association is still poorly understood. It is still
intensively debated whether depression is simply a
prodromal initial state of dementia or an independ-
ent risk factor for dementia years before the onset of
dementia. Further, a number of other issues are
unclear and have only recently attracted some
attention. Does the type of depression play a role?
Does the type of dementia play a role? Does anti-
depressant treatment for depressive episodes play a
role? The aim of the present review was to analyse
findings from recent studies in relation to these
questions.
OF DEMENTIA OR AN INDEPENDENT RISK
FACTOR FOR DEMENTIA?
This is the main topic of debate, which is not easy to
clarify. Symptoms of depression and symptoms of
dementia overlap. Consequently, apparent depres-
sion symptoms such as social withdrawal and
apathy could be the earliest symptoms of dementia.
Alternatively, persons with insight into the early
deterioration of their memory could develop depres-
sed mood months or even years before the date
when dementia was recognized or diagnosed [8].
Therefore, it is not surprising that depression may
Psychiatric Center Copenhagen, Rigshospitalet, University Hospital of
Copenhagen, Denmark
Correspondence to Professor Lars Vedel Kessing, MD, DMSc,
Psychiatric Center Copenhagen, Rigshospitalet, University Hospital of
Copenhagen, Blegdamsvej 9, Department 6233, DK 2100 Copenhagen
Ø, Denmark. Tel: +3545 6237; fax: +3545 6218; e-mail: lars.vedel.
kessing@regionh.dk
Curr Opin Psychiatry 2012, 25:457–461
DOI:10.1097/YCO.0b013e328356c368

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 Geriatric psychiatry
be the first sign of dementia, that is, a prodromal
state. It is more interesting and unclear whether
depression starting many years before the onset of
dementia is a risk factor. This issue has been in focus
in rather few studies. The Mirage study was the first
larger study to investigate the temporal association
between depression and dementia [8]. Interestingly,
depression symptoms were significantly associated
with Alzheimer’s disease even when the onset of
depression preceded the onset of Alzheimer’s disease
by more than 25 years [odds ratio (OR) 1.71; 95%
confidence interval (CI) 1.03–2.82]. This finding
& &&
was recently replicated in two studies [3 ,5 ] but
& &
disproved in two others [4 ,9 ]. In the Women’s
Health Initiative Memory Study including women
only, remote history of depression, without current
depression, was associated with subsequent risk of
probable dementia during a mean follow-up period
of 5.4 years (hazard ratio 2.08, 95% CI 1.15–3.78)
&
[3 ]. The second confirmatory study was conducted
among Kaiser Permanente members in California
&&
[5 ]. Among patients with midlife depressive
symptoms only, that is, without later depressive
symptoms, the risk of dementia during 6 years of
follow-up was increased by 20% (hazard ratio 1.19,
95% CI 1.07–1.32). The same tendency was found
between midlife depressive symptoms and vascular
dementia, however, not statistically significant,
but not between midlife depressive symptoms and
&& &
Alzheimer’s disease [5 ]. Two studies, with 4 [9 ]
&
and up to 15 years of follow-up [4 ], did, however,
not find associations between early life depression
and dementia.
These contradictory findings are most likely due
to two overall issues: the first issue is regarding the
methods used for assessing depressive and cognitive
symptoms, and the second one is regarding issues
relating to the type of depression and the type of
dementia. Regarding the first issue, it is evident
that retrospective assessment of prior depressive
symptoms and episodes over a lifetime period is
an unreliable method. The prevalence of lifetime
psychiatric disorders, including depression, among
younger individuals (aged up to age 32 years) is
approximately half in retrospective as compared
with prospective data [10]. It is evident that this
recall error is even higher among the samples of
elderly people aged 65 years or more included in the
studies of depression and dementia, due to three
factors. They are older, they have to recall a longer
lifetime period and they may suffer from prodromal
symptoms of dementia (of either depressive or
cognitive nature). Thus, retrospective assessment
of prior depression results in a substantial mis-
classification, increasing the risk of finding no
statistically significant associations between prior
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depression and dementia. A few register-based
studies have avoided this recall error by using
routinely longitudinally recorded data confirming
an association between a history of depression
and increased risk of dementia [11,12]. Such an
association was, however, not found in the before-
&&
mentioned study by Barnes et al. [5 ], partly using
Kaiser Permanente register data.
Apart from the fundamental limitations in
retrospective assessment of prior depressive symp-
toms/depression, there are a number of issues relat-
ing to the type of depression and the type of
dementia (second issue) that may add to explaining
the contradictory findings. These latter issues are
rarely considered in the studies. Depressive illness
may include different subtypes of the illness with
varying pathogenesis. The same is true for dementia.
DOES THE TYPE OF DEPRESSION PLAY A
ROLE?
Depression presents in a number of subtypes, such
as late versus early-onset depression as well as single
versus recurrent depression.
Late versus early onset of depression
Late-onset depression is typically defined as onset of
first depressive episode following age of 65 years.
Geriatric depression is often considered to be a
separate clinical entity [13] that is related to struc-
tural brain abnormalities [13] of vascular origin [14],
and phenomenologically characterized by more
severe depressions and a higher prevalence of psy-
chosis than patients with early onset [15]. Although
a few studies have focused on late-onset depression
& &&
[4 ,5 ], the dating of the first-onset depressive epi-
sode was most likely inaccurate as the information
was collected retrospectively (mainly) based on
recall of the participating individuals. Both studies
concluded that late-onset depression may be an
early manifestation of dementia rather than a risk
factor many years before the onset of dementia.
However, these findings may be more a matter of
definitions related to late-onset depression than
of cause. Due to the shorter time span between
onset of first episode of depression and date for
diagnosis of dementia in late-onset depression, it
is per se more likely that this type of depression may
be an early manifestation of dementia rather than a
risk factor many years before the onset of dementia.
There is a need to investigate whether vascular risk
factors such as cigarette smoking, diabetes and car-
diovascular disease mediate the association between
late-onset depression and subsequent dementia.
Preliminary results from a short-term study suggest
that high vascular risk scores predict poorer
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November 2012

cognitive function following treatment for depres-
&
sion [16 ].
Single depressive episode versus recurrent
depression
Two-thirds of patients with a first moderate to severe
depressive episode develop recurrent episodes; a
third do not. If depressive episodes confer a risk
for insults of the brain and for the development
of cognitive symptoms and dementia, patients with
recurrent depressive episodes would be expected to
be associated with a higher risk of cognitive abnor-
malities than patients with a single depressive epi-
sode. Nevertheless, none of the above-mentioned
studies have differentiated between these subtypes
of depressive disorder, but rely on measures of
depressive symptoms at one time point only. In a
previous study using hospital register-based data
from our group, we found that patients with many
prior hospitalizations for depression had increased
risk of subsequently developing dementia compared
with those with one hospitalization for depression
only [17]. In fact, the rate of dementia was sig-
nificantly related to the number of prior affective
episodes leading to admission. On average, the rate
of dementia increased 13% with every episode
leading to admission with depression [17]. These
findings have subsequently been confirmed in a
prospective study on depression and dementia in
the community in which patients were asked about
self-reported depressive symptoms at 1–2-year inter-
vals [18]. Each depressive episode was associated
with a 14% increase in risk of subsequent develop-
ment of dementia.
Such an association with the number of prior
depressive episodes has also been found in some
cross-sectional studies on cognitive function in
the remitted state of unipolar depression ([19–22];
&
for a review see [23 ]), whereas others have found an
association between the cumulative duration of
depressive episodes and cognitive function in the
&
remitted state [24 ]. Further, it is possible that
severity of the depressive episodes, such as psychotic
depression, may have a deleterious effect on brain
&
function and cognitive function [24 ].
Finally, a few studies from our group have found
that bipolar depression is associated with increased
risk of dementia [11,12].
DOES THE TYPE OF DEMENTIA PLAY A
ROLE?
It is often difficult to discriminate clinically between
subtypes of dementia due to overlap in pathogen-
eses, course and symptoms (e.g. vascular dementia
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Depression and the risk for dementia Kessing
and Alzheimer’s disease), and previous studies have
not revealed clearly whether depression is associated
more with one subtype than with another [1,2].
More recent studies have provided contradictory
findings and interpretations. Barnes et al. [5 ]
&&
suggested, based on their findings, that recurrent
depression during lifetime may be a risk factor for
vascular dementia, whereas first depression in late
life may reflect the first symptom of dementia,
particularly Alzheimer’s disease. This was, however,
&
contradicted by the study by Lenoir et al. [9 ], who
found that depressive symptoms in late life pre-
dicted increased risk of vascular dementia during
4 years of follow-up but not Alzheimer’s disease.
This latter finding of depressive symptoms reflecting
a prodromal phase of vascular dementia has
indirectly been supported by other recent findings.
Memory impairments often precede other cognitive
dysfunction in Alzheimer’s disease, but a recent
study found that depressive symptoms at baseline
were associated with cognitive decline within exec-
&
utive control, but not memory [25 ], in accordance
with prior findings [26]. Overall, these contradictory
findings emphasize the importance of studies on the
pathogenesis mediating the association between
depression and dementia. We recently failed to
find an association between amyloid, which is
associated with Alzheimer’s disease, and the number
of prior depressive episodes in a cross-sectional
study of patients remitted from depressive disorder
&
[27 ], but the included patients had had rather few
prior depressive episodes on average, decreasing the
statistical power of the study.
DOES ANTIDEPRESSANT TREATMENT
FOR DEPRESSIVE EPISODES PLAY A
ROLE?
A number of observations suggest that antidepress-
ants may have neuroprotective abilities by increas-
ing the proliferation of neural progenitors in the
subgranulate zone of the hippocampus, as well as
the survival of these newborn neurons [28,29], and
therefore may improve memory processes and cog-
nition [30]. Further, it has been suggested that treat-
ment with a selective serotonin reuptake inhibitor
(SSRI) may improve cognitive function and daily
living in patients with Alzheimer’s dementia [31].
It is consequently an appealing hypothesis that
long-term continued treatment with antidepress-
ants may decrease the risk of developing dementia
among individuals with recurrent depression. This
hypothesis is not easy to test. It would be difficult to
undertake a prospective longitudinal and controlled
study investigating the association between anti-
depressants and dementia, as a large number of
www.co-psychiatry.com 459
 Geriatric psychiatry
patients with depression without symptoms of
dementia and with and without antidepressant treat-
ment would have to be followed longitudinally for at
least 5–10 years. An alternative approach is to use
register-based data, as done in two recent studies
from our group. In the first study we identified all
individuals in a nation-wide database who had been
prescribed antidepressants in Denmark during a
period from 1995 to 2005 [32]. These data were linked
to nation-wide data on diagnoses of dementia. As
expected, persons who purchased antidepressants
once (N ¼ 687 552) had a two to three times increased
rate of dementia compared with persons unexposed
to antidepressants (N ¼ 779 831), as these individuals
suffered from depressive disorders mainly. Never-
theless, the rate of dementia changed over time;
thus, during the initial prescription periods the
rate increased with the number of prescriptions,
but continued long-term antidepressant treatment
was associated with a reduction in the rate of
dementia, although not to the same level as the
rate for the general population. This pattern was
found for all classes of antidepressants (SSRIs, newer
non-SSRI antidepressants and older antidepressants).
All findings were replicated in sub-analyses with
Alzheimer’s disease as outcome. In the second study,
a population of patients discharged from psychiatric
healthcare service with a diagnosis of depression at
&
their first psychiatric contact was identified [33 ]. The
rate of dementia was decreased during periods with
two or more prescriptions of older antidepressants
compared with the rate during the period with one
prescription of older antidepressants [relative risk
(RR) 0.83, 95% CI 0.70–0.98]. This finding was
replicated with Alzheimer’s disease as the outcome
(RR 0.66, 95% CI 0.47–0.94) but not with dementia
of other kinds as the outcome (RR 0.88, 95% CI
0.73–1.06). In contrast, during periods with con-
tinued use of SSRIs or newer non-SSRIs the rate of
dementia was not decreased, regardless of the sub-
type of dementia.
On the basis of the findings from the two studies
it can be hypothesized that continued treatment
with SSRIs or newer non-SSRIs may prevent develop-
ment of dementia in patients with less severe
depressive disorders, as found in the first study
[32], but not in patients with more severe depressive
disorders resulting in contact with psychiatric hos-
&
pital services, as found in the second study [33 ].
Among patients treated in psychiatric hospital
services, treatment with SSRIs or newer non-SSRIs
may not counterbalance the increased risk of
developing dementia related to each new affective
episode [17,19]. In contrast, it is possible that
features related to older antidepressants such
as tricyclic antidepressants may explain why
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continued use of these drugs was associated with
decreased risk of developing dementia in the long
&
run in the second study [33 ], which included a
sample of patients with melancholic depression,
depression with psychotic features and treatment-
resistant depression. Thus, studies on in-patients
with depression, including studies from Denmark
[34–36], show increased efficacy of the tricyclic
antidepressant clomipramine for depression com-
pared with SSRIs [37] or other antidepressants [35].
Interestingly, we have in other studies (with
similar designs as in the two studies mentioned
above) found that continued use of lithium, which
also seems to possess neuroprotective abilities, was
associated with decreased risk of developing demen-
tia in bipolar disorder [38,39].
The above-mentioned associations between
drugs, depression and dementia should be regarded
as preliminary findings and warrant confirmation in
other populations and study designs.
CONCLUSION
A large of body of studies has confirmed the associ-
ation between depression and subsequent demen-
tia. As always within biology, reality turns out to be
more complex than first expected. This review has
shown that a number of important factors have to be
considered to improve knowledge on the associ-
ation between depression and dementia. Most
evidently, in addition to a number of methodo-
logical aspects, the type or nature of depression
and dementia studied, as well as the influence of
antidepressants and other treatment modalities,
should be clearly characterized. Recent studies
suggest that some forms of depressive illness may
constitute a long-term risk factor for development of
dementia, whereas the onset of depressive symp-
toms for the first time in old age may reflect a
prodromal phase of dementia. Additionally, recent
studies suggest that long-term treatment with anti-
depressants may influence the associations. The
types of depression and dementia as well as the
types of treatment have to be characterized in more
detail and to be taken into account when designing
future studies. Further studies on the pathogenesis
mediating the association between depression and
dementia are crucially needed.
Acknowledgements
None.
Conflicts of interest
Lars Vedel Kessing has been a consultant for Bristol-
Myers Squibb, Eli Lilly, Lundbeck, AstraZenica, Pfizer,
Wyeth, Servier.
Volume 25
Number 6
November 2012

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