Journal of the Neurological Sciences 226 (2004) 53 58

www.elsevier.com/locate/jns

Is poststroke depression a vascular depression?

Sebastian Dieguez*, Fabienne Staub, Laure Bruggimann, Julien Bogousslavsky
Neurology Department, Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon 46, 1011 Lausanne, Switzerland
Available online 7 October 2004

Abstract
As we learn more about the relationships between depression and cerebrovascular disease (CVD), a complex picture is emerging in which
the chain of causality seems to spiral on itself: progressive or focal brain damage, cognitive impairment, depressive symptoms, dementia, and
cardiovascular diseases, all seem to be liable to lead to one or another. Stroke may lead to depression, and the inverse may also be true.
Depression may lead to cognitive impairment and cardiovascular diseases, which in turn may lead to subtle brain impairment, thereby causing
more depression and cognitive impairments, and so on. In this presentation, we provide a rapid glance at the complexities of such issues.
D 2004 Elsevier B.V. All rights reserved.
Keywords: Stroke; Poststroke depression; Vascular depression; Risk factors; Mood; Dementia

1. Introduction
Depression is a frequent and important poststroke
complication, with a negative influence on quality of life,
because it is associated with increased disability, cognitive
impairment, and mortality [14]. The so-called bpoststroke
depressionQ (PSD) has been the focus of many studies in the
last decades, and researchers have investigated various
potential mechanisms to explain the relationships between
stroke and depressive symptoms. These are often presented
as direct causal effects, involving the influence of location
and lateralization of lesion, the burden of neurological and
cognitive impairment, or some form of psychological coping
with the stressful event. Indeed, stroke is one of the few
conditions listed in the DSM-IV as a direct cause of
depression. PSD is such a concern that a multidisciplinary
consensus panel, examining more than 1900 clinical research
articles on stroke rehabilitation, explicitly proposed as one of
their four key recommendations that special surveillance was
ascribed to the development of depression [57].
Cerebrovascular diseases (CVDs) were thereafter considered more globally as potential factors in the genesis of

* Corresponding author. Tel.:+41 21 314 12 63; fax:+41 21 314 12 44.

E-mail address: sdieguez@hospvd.ch (S. Dieguez).
0022-510X/$ - see front matter D 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jns.2004.09.012

late onset depression, an approach which has been dubbed

bthe vascular depression hypothesisQ and is now supported
by clinical and radiological observations. More recently, in a
dramatic reversal of the chain of causality, researchers have
begun to publish large studies that highlight the role of
depressive symptoms per se as risk factors for the development of subsequent CVD like stroke, an idea we refer to as
bprestroke depressionQ. Taken together, these different
approaches give us a complex picture of the relationships
between brain function, vascular activity and mood,
relationships that appear to be reciprocal rather than
sequential. At this state of knowledge, many questions
remain open, one of them being the title of this presentation.

2. Poststroke depression
2.1. Definition, diagnosis, and prevalence
PSD has been defined as bdepression occurring in the
context of a clinically apparent stroke (as opposed to silent
CVD)Q [3]. It is still a matter of controversy whether
depression after stroke should be considered as an
equivalent of endogenous depression (ED, also called
bfunctional depressionQ, that is, depression occurring without acute brain injury), in both its phenotype and neuro-

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anatomical bases [8,9]. Nevertheless, researchers generally

agree to rely on DSM-IV criteria for major and minor
depression, whether endogenous or following stroke [10].
Methodological limitations include difficulties in obtaining
reliable self-ratings in acute stroke populations due to
aphasia, anosognosia, or intellectual confusion. In addition,
multiple diagnostic confounders also following stroke
(anxiety [11], catastrophic reactions [12], posttraumatic
stress disorder [13], fatigue [10], apathy [14], etc.) should
be considered.
It has been remarked that bthe prevalence of poststroke
major depression varied up to fourfold across studiesQ [3].
For example, in one review of the literature, Gordon and
Hibbard [15] found prevalences varying from 25% to 79%.
This is of course largely due to important methodological
variations across studies, involving assessment tools, width
and nature of the population studied, evaluation-time after
stroke, controls used, inclusion and exclusion criteria, etc. In
a recent review, Robinson [4] arrived at a figure of 19.3%
for major and 18.5% for minor depression, based on pooled
data using a large array of published studies. This is higher
than prevalence rates for major depression in the general
population, which is estimated at 10% over a 12-month
period. Despite a lack of consensus in the literature, it is
widely accepted that major depression after stroke is a
common occurrence and of sufficient concern to be
recognized as a key factor in rehabilitation and outcome
after stroke [3,7].
Authors have pointed to a host of factors possibly
associated with PSD. In a review of 13 papers, Carota and
Bogousslavsky [16] have sorted some of these factors
according to their significance (negative or positive), as
related to the presence of PSD. Table 1 shows that, except
for functional outcome, it has been difficult to find a single
good predictor of PSD.
2.2. Mechanisms
The etiopathogenesis of PSD has also been hotly
debated. Positions on this issue have tended to coalesce
Table 1
Review of 13 studies regarding the significance (or lack thereof) of the
association of 11 factors with PSD (see Ref. [18] for details)
Factors
Age
Gender (F)
Prior stroke
Prior disability
Prior depression
Stroke severity
Stroke side
Lesion volume
Anterior circulation
Cognition
Functional outcome

Significance in 13 studies
Significant

Non-significant

6
5
3
0
3
5
1
3
4
6
10

6
6
2
2
1
0
7
2
2
2
1

around two explanatory poles: authors who insist primarily

on a biological mechanism, whereby ischemic insults
directly affect neural circuits involved in mood regulation
[17]; and authors who rather focus on reactional psychosocial and stress mechanisms [2,18,19].
Among the latter authors, Gainotti et al. [18] have argued
that the phenomenology of major PSD, with its high
prevalence of reactive diurnal mood variations, anxiety,
emotionalism, and catastrophic reaction is distinguishable
from the phenomenology of ED, which is characterized by
morning prevalence, depressive mood, suicidal thoughts,
and guilt feelings. In addition, mood in subjects with PSD
appears to be linked more to handicaps and disabilities than
to lesion location. They conclude that their data are
consistent with a psychological model of PSD, rather than
with a neurochemical one, based on a reactive response to a
particularly stressful event (Ref. [20], see also Ref. [21]).
In accordance with a psychosocial model, occurrence of
a bmajor life eventQ before stroke has been shown to be a
risk factor for PSD [22]. Other psychosocial risk factors
include a previous history of major depression, a neurotic
personality style, disability, and social isolation [3]. In
addition, others have highlighted the importance of psychological treatment in PSD and thus the need to take into
account personality and psychosocial factors [23].
Most of the arguments directed against a strict biological
view of PSD mention the contradictory evidence available
in this area; for example, there is as yet no consensus on the
role of lesion location in PSD [24].
However, hints that PSD may be mediated primarily by
biological mechanisms come from a variety of data. First, it
is important to underscore the fact that ED itself is
underpinned by brain and cognitive abnormalities, specifically basal ganglia and prefrontal dysfunctions. This is well
established both from imaging and clinical data [25]. Early
studies focused on whether stroke survivors were more
likely to suffer from depression than patients with other
ailments not involving acute brain injury. For instance, in
1977, Folstein et al. [26] found that depression was more
frequent in a stroke population than among orthopedic
patients presenting similar levels of physical disability. They
concluded that PSD could not be considered a simple
emotional reaction to a reduction in autonomy. In a more
recent study, depressive symptoms were found to be more
severe in stroke patients and patients with symptomatic
carotid stenosis, than in patients with peripheral vascular
disease [27].
However, other researchers have found no difference in
depression scores of stroke patients versus other conditions.
For example, in a recent study, Aben et al. [28] have shown
that, after controlling adequately for age, sex, and level of
handicap, there was no difference in the incidence of
depression after stroke or myocardial infarction, thus
challenging the idea that specific cerebral factors play a
crucial role in the pathogenesis of PSD. Ironically, as will be
shown in the next section, comparing stroke patients with

S. Dieguez et al. / Journal of the Neurological Sciences 226 (2004) 5358

myocardial infarct patients with regard to subsequent

depression may precisely be a contestable method, as
acknowledged by the authors of the study themselves, for
the following reason: bthe increased incidence of depression
after stroke and myocardial infarction may reflect other
factors shared by the two conditions. One possible
mechanism is that generalized damage to the vascular
system in the brain may subsequently affect mood regulatory processesthe so-called vascular hypothesis [. . .]
This more general vascular mechanism could play a role in
both myocardial infarction and stroke (p. 584)Q. Hence,
bspecific cerebral factorsQ may anyway be involved in
depression following myocardial infarction.
Finding a precise brain localization responsible for
depression has been elusive and the topic is currently still
under debate. Initially, much discussion was derived from
the frequent involvement of left anterior lesions in the
development of PSD, but recent publications, including one
large meta-analysis, have somewhat downplayed this
enthusiasm, being unable to find a reliable anatomic
correlates of PSD [25,29]. Primarily one research group,
led by Robinson [4], has maintained the localizationist
approach. He recently fought back with his own metaanalysis, which states that, during the first 2 months after an
acute stroke, left frontal and left basal ganglia lesions were
indeed significantly more frequent among patients with
major depression compared with any other lesion. Even
more recently, a team led by this same author confirmed his
previous finding of a significant correlation between
severity of depression and proximity of the lesion to the
left frontal pole, for patients who were less than 6 months
poststroke [30]. The mechanism proposed is a disruption of
monoaminergic pathways.
Other arguments advanced in favor of a primarily
biological mediation in PSD are in sharp contrast with
those arguing for a psychological reaction. For example, it
has been claimed that clinical symptoms in PSD and ED are
similar (as are biological markers such as the dexamethasone suppression test) and that there is no clear correlation
between the severity of depression and the degree of the
neurological deficit [31].
Depression occurring in patients with anosognosia seems
to be a compelling case against a purely psychological
mechanism because no bconsciousQ psychological reaction
can account for the depressed mood. This does not
necessarily occur in right-sided lesions only, and has been
described in left subcortical lacunar infarcts as well [32].
However, anosognosia accompanying PSD is rare [33].
Subcortical lesions have also been reported as favoring
the emergence of depressive symptoms, especially when
left-sided [34]. Depressive signs following subcortical
lesions are thought to be due to disruption of frontal
subcortical circuits, which in turn leads to depletion in
cortical biogenic amines [35]. More often than not,
subcortical PSD is accompanied by cognitive impairments.
This association of PSD and cognitive impairment is well

55

documented. In a 1-year prospective study of 106 first-ever

stroke patients, Kauhanen et al. [36] found that severity of
depression correlated negatively with performance on
neuropsychological measures of nonverbal problem solving,
memory, attention, and psychomotor speed at 12 months
after stroke. With the same population, this team also
showed a strong link between the presence of dysphasia and
a higher risk of major depression [37]. Of course, we are left
with the question of whether it is depression that causes
cognitive and functional impairment or cognitive impairment that leads to depression (although some evidence
points to depression as the main factor leading to, or
aggravating, cognitive impairment due to stroke. See, for
example, Ref. [38]).
It has also been proposed that, while left-sided lesions
often lead to PSD, right-sided lesions are mostly associated
with poststroke euphoria, mania, or even bipolar disorder
[3,4,39].
As will be developed in the next section, more
compelling evidence in favor of the importance of biological factors in depression, than for strict localization, is
provided by the notion of vascular depression (VaD). Silent
infarctsthat is, cerebral lesions of which the patients are
unaware because they are largely asymptomaticcan cause
depression independently of psychological mechanisms
[40,41].
Biological and psychological factors may have a differential impact on PSD depending on the time course of stroke
outcome. It is possible that lesion location is strongly
associated with the development of early PSD and that
psychological factors have more weight in nonacute, lateronset PSD [42]. In the end, it must be said that most authors
acknowledge a multifactorial origin of PSD because it
always arises from a complex entangled web of prior life
events, coping styles, and idiosyncratic neuronal functioning and structure.
2.3. Vascular depression
In contrast with PSD, which occurs by definition after an
acute and focal vascular event, vascular depression is
considered to be a consequence of chronic ischemic lesions
[43]. Here is how it was originally defined: bDepression in
the presence of vascular risk factors, accompanying neuropsychological deficit and distinct localized brain pathology
seen on structural imagingQ [40,44].
The bvascular depressionQ hypothesis states that lateonset depression (over 50 years of age) might often be due
to vascular damage to frontal-subcortical circuits implicated
in mood regulation and cognition [45]. Indeed, patients with
late-onset depression have been found to present more
cognitive and neuroradiological abnormalities, greater disability, lower familial prevalence of mood disorders, and
less personality dysfunction than elderly people with earlyonset depression, all pointers to a biological origin of what
often appears clinically as a brutal mood transformation in

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elderly patients [46]. Numerous imaging studies of lateonset depression have fairly consistently shown abnormalities, referred to as bwhite matter hyperintensitiesQ (WMHs),
especially in the periventricular areas and the striato-frontal
circuits, including ischemic damage to the dorsolateral
prefrontal cortex. These WMHs are of crucial clinical
importance, as they are linked to poor response to treatment,
residual cognitive impairment, increased relapse rate, and
progression to chronic depression. The specific mechanisms
of vascular depression are poorly known and presumably
involve an association with age, increase in atheromatous
vessels, vascular risk factors, and CVD [4751].
An important point is that these vascular lesions may
or may not be clinically evident before the appearance of
depressive symptoms, as is evident from the term bsilent
cerebral infarctQ introduced by Fujikawa et al. [41], in
order to refer to the structural brain abnormalities related
to major depression in the absence of cognitive or
functional deficits. Here, depressive and cognitive symptoms are seen as arising from related neurobiological
processes which involve the progressive or sequential
disruption of subtle connections important for mood
processing and executive functions.
It should come as no surprise that vascular depression has
been closely linked to dementia, as researchers have
acknowledged since a long time the existence of a relationship between depressive and dementia-like symptoms, as
with bpseudodementiaQ [52] or breversible dementiaQ [53]. A
recent study by Fuhrer et al. [54] showed that depressive
symptoms increase the risk of developing dementia during an
8-year follow-up period, although this effect was noted only
in men. Furthermore, the risk for dementia was 50% higher in
depressed hypertensive men than in nonhypertensives. In
addition, elders who developed vascular dementia had more
depressive symptoms than persons without dementia or with
AD. The authors conclude that vascular disease may lead to
depression and that sometimes this depression can progress
into dementia. Importantly, the relationships between
vascular disease, depression, and dementia need not be
sequential and direct, but rather reciprocal [46].

3. Is depression a risk factor for ischemic stroke?

We now turn to the topic of depression as a risk factor
in itself. Well-known cerebrovascular risk factors, from the
AHA (American Heart Association) are, hypertension
(related primarily to hemorrhagic stroke), smoking, diabetes, asymptomatic carotid stenosis, sickle cell disease,
hyperlipidemia, atrial fibrillation, and lifestyle factors.
Among these blifestyle factorsQ, a depressive mood is
known as a risk factor for coronary heart disease in
general [5557], so it appears that a good case could be
made for depression per se as a predictor of later stroke.
This is indeed what a number of studies have found [58
64]. For example, a recent prospective study by May et al.

[59] with a cohort of 2201 men found that the relative

risk of fatal stroke was increased by a factor of 3.36 in
individuals presenting significant depressive symptoms at
baseline. A figure of 2.6 was found in another study [58]
that carefully controlled for heart disease, hypertension,
diabetes, and current and previous use of tobacco. This
finding was not altered by medication used in the
treatment of depressive disorder at baseline. In a followup of 29 years, Everson et al. [61] reported that
individuals presenting five or more symptoms of depression at baseline were 50% more likely to die of a strokerelated cause during this time. A Japanese study found
that depressive symptoms were only predictive of ischemic and not hemorrhagic stroke [64]. Therefore, it seems
that depression is a serious risk factor for stroke, not
necessarily related to other classic risk factors.
Moreover, by exacerbating vascular morbidity and
increasing mortality from vascular diseases, depression
may contribute to the development of vascular dementia,
and perhaps to dementias of other etiologies. Clinicians
know well that the first signs of dementia are often preceded
by depressive symptoms. This may be indicative that the
same underlying vascular impairment is common to both
depression and dementia [65]. As Alexopoulos [46] puts it,
bdepression may be both a risk factor and a prodromal
symptom of dementing disordersQ.
Hypothetical mechanisms that account for bprestroke
depressionQ have been derived from several findings in the
biology of depression involving metabolic changes that may
lead to brain impairment [46,55]. Depressive symptoms are
related to increased platelet activity (related to increased
autonomic sympathetic activity), increased serotonin-mediated platelet activation, and excessive secretion of glucocorticoids. They also predict later hypertension incidence (a
possible pathway to a stroke event) and promote subtle
lifestyle changes that have an impact on conventional risk
factors of stroke. It may also be that the association of
depressive symptoms and later onset of ischemic stroke is
only an bepiphenomenonQ, arising from underlying vascular
disturbances cumulating through time. Another line of
research focusing on brain plasticity mechanisms suggests
that stress-related hormones reduce the production of
neurotrophic factors and inhibit neurogenesis, both of which
are obviously liable to increase vulnerability to vascular
changes [46].

4. Conclusions
At this stage, it seems that the question of whether PSD
is of organic or psychological origin has become obsolete.
We have seen that organic dysfunctions, even subtle ones
that do not produce neurological symptoms, are involved
in the development of depressive symptoms. On the other
hand, we now have evidence that depressive symptoms per
se are involved in the onset of cardiovascular diseases and,

S. Dieguez et al. / Journal of the Neurological Sciences 226 (2004) 5358

hence, stroke-related disorders. Therefore, depression is

both a cause and a consequence of CVD. Bearing all of
these elements in mind, we can try to answer the question
asked in the title of this presentation: Is poststroke
depression a vascular depression? Of course, if we adhere
to a strict definition of vascular depression, it seems that
PSD does not cover the same idea at all (the former
implies silent vascular lesions in depressive elders, and the
latter a focal ischemic insult leading to depression).
However, in our opinion, bvascular depressionQ should be
viewed from a larger perspective, one that integrates a
bidirectional point of view: as there are vascular aspects
involved in depressive symptoms, there are mood aspects
involved in vascular disorders. Therefore, we can answer
yes, in this wider sense, PSD is a vascular depression, but
we need to think in a nonlinear fashion and see these
problems as the outcome of complex interrelating factors,
or as Robinson puts it, bthe inextricable relationship
between physical and mental disordersQ [4].

Acknowledgment
The authors wish to thank Sarah Viollier for kindly
reviewing the manuscript.

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