NEUROPSYCHIATRIC PRACTICE AND OPINION

Does Stroke Cause

Depression?
Constantine G. Lyketsos, M.D., M.H.S.
Glenn J. Treisman, M.D., Ph.D.
John R. Lipsey, M.D.
Philip L.P. Morris, M.D.
Robert G. Robinson, M.D.
Research into many brain diseases, including stroke,1
Alzheimers disease,2 Parkinsons disease,3 epilepsy,4
Huntingtons disease,5 and AIDS,6 has shown significant associations between these conditions and the presence of depressive disturbances. These associations are
important for a variety of reasons. First, the occurrence
of depression in neurologic disease is a natural experiment whose study continues to shed light on our understanding of the role of the brain in depressive illnesses. Second, the co-occurrence of depression and
neurologic disease magnifies morbidity. Third, treatment of depression in neurologic disease may greatly
improve prognosis.
Perhaps the most interesting issue regarding the association between depression and neurologic disease is
whether depression is caused by neurologic disease. Two
general types of causal links should be distinguished. In
the first, depression arises as a psychological reaction to
the impairments or social disruption produced by the
neurologic disease, in the same way that depression
might arise in any individual faced with the adversities
produced by a serious disease. In the second, depression
is a specific symptom of the neurologic disease and is
intimately tied to the pathophysiology of the disease.
The relationship between stroke and depression has received sufficient investigation to make it a suitable
model in discussing such potential causal relationships.
In this article we review research on depression and
stroke to illustrate how to approach causal links between neurologic disease and mental syndromes. Our
major conclusion is that stroke lesions, under certain circumstances, cause depression through a direct but unknown pathophysiologic process.

BACKGROUND
Dr. Allan House recently has argued7 that there are few
data to support the hypothesis that depression is a spe-

JOURNAL OF NEUROPSYCHIATRY

cific complication of stroke. Although he did not

overtly acknowledge his assumptions, he began with
the premise that depression is a natural psychological
reaction to the adversity of stroke.
Dr. House contested the existence of a specific syndrome of poststroke depression, which has been proposed by Robinson and others.1 His argument against
the poststroke depression hypothesis is based on the refutation of certain predictions that he believes flow naturally from the hypothesis.
Specifically, Dr. House has postulated7 that if there
were such a specific complication of stroke as poststroke depression, then three things would be expected. First, the clinical picture of depression after
stroke (such as its constituent symptoms or frequency)
would be different from depression in the absence of
stroke or after other general medical conditions. Second,
depression would have a different etiology after stroke.
Third, depression associated with stroke would have
different characteristics in response to treatment. After reviewing the empirical evidence in these three areas,
Dr. House concluded that none of these predictions has
been consistently supported by the existing literature.
He implied that we cannot, as yet, prove that depression
is a specific complication of stroke.
We disagree with Dr. Houses postulates and feel that
he has finessed the central issue in this debate. The critical question regarding the association of depression and
stroke is not whether poststroke depression fulfills
Dr. Houses postulates, but rather, What is the cause of
depression after stroke? Dr. Houses criteria to assess
causality are inadequate to make a judgment about this
issue.
For some patients, depression, anxiety, and other
symptoms commonly follow stroke and are indicative
of the individual coming to terms with an adverse event.
These natural human emotions do not imply a particular pathophysiology of the stroke or the depression. In
the sense that they resemble symptoms seen after any
adverse event, they are not specific to stroke. Their cause
is not the stroke per se, but rather the characteristics of
the stroke that make it an adverse event to that particReceived April 4, 1997; revised May 20, 1997; accepted October 26,
1997. From the Neuropsychiatry and Memory Group, Psychiatry and
Behavioral Sciences, Johns Hopkins Medical Institutions, Osler 320,
The Johns Hopkins Hospital, Baltimore, Maryland 21287; e-mail:
kostas@welchlink.welch.jhu.edu. Send correspondence to Dr. Lyketsos
at the above address.
Copyright q 1998 American Psychiatric Press, Inc.

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NEUROPSYCHIATRIC PRACTICE AND OPINION

ular individual, at that particular time, in his or her particular life.
In other patients, a different kind of depression
emerges after stroke. This is major depression, a welldefined disturbance, which most psychiatrists operationalize as a syndromic category8 based on disjunctive
criteria (5 of 9 possible symptoms). These criteria characterize severe depression due to genetic causes (probably multiple types), environmental stressors, personal
vulnerability, or symptomatic response to physical factors ranging from reserpine medication to structural lesions. It is the syndrome of major depression after stroke
that we propose might at times be caused directly by the
pathophysiology of stroke. Dr. House suggested that
clinical presentation, pathophysiological mechanisms,
and response to treatment would all be unique if major
depression was a specific consequence of stroke. However, the syndrome of major depression can probably be
caused by a range of pathologies that affect the brain
as is suggested by work in other diseases26as well as
by genetic predispositions. One would not a priori predict that poststroke major depression would manifest
itself in a unique clinical presentation, any more than
one would presume that every form of pneumonia
could be distinguished on clinical examination alone. In
fact, it was shown by Lipsey et al.9 that poststroke major
depression has a very similar clinical presentation to
major depression in elderly patients without structural
brain lesions.
Dr. Houses criterion of unique response to treatment
is similarly inappropriate. For instance, cases of congestive heart failure arising from different causes may respond as well to the same diuretic, just as antihypertensive agents are often effective across a wide etiologic
spectrum. Antidepressant medication has been shown
in controlled treatment trials to be effective in treating
disorders ranging from pure familial depressive disorder to social phobia to obsessive-compulsive disorder.
The fact that poststroke depression responds to antidepressant therapy provides no evidence for or against a
causal relationship between stroke and depression.
Dr. Houses criterion for specificity is somewhat closer
to the mark. We agree that if a specific form of poststroke
depression exists, it by definition results from some
mechanism directly related to the brain injury. However,
it is clear that depression following stroke might at times
have other (or even multiple) causes.
It is precisely the similarity of major depression after
stroke to major depression in other settings that raises
doubts about whether major depression after stroke is
always simply a human reaction to the adversity brought
on by illness. A human reaction to adversity is typically
universal and nonspecific. Major depression after stroke

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has not been shown to respond to nonspecific psychological or psychosocial interventions,7 but it has been
shown to respond to specific pharmacologic treatment
for depression.10,11 If a patient developed chest pain after stroke, along with joint pain, anxiety, and indigestion, we might think of the chest pain as a somatization of his or her distress and attempt to treat it with a
psychological intervention. If, however, a patient developed chest pain with radiation to the left hand, accompanied by nausea, we might recognize the syndrome of
angina and be concerned that the patient has heart disease. We make a similar argument about depressed
mood (or anhedonia) as part of a major depressive syndrome, as opposed to depression as part of nonspecific
distress and demoralization.

CRITERIA FOR A CAUSAL RELATIONSHIP

If Dr. Houses criteria assessing causal associations are
inadequate, what criteria are more appropriate? Susser12
has persuasively argued that the demonstration of causality rests on three principles linking the cause to the
effect: association, temporal order, and direction. The
proposed criteria, as applied for neuropsychiatric disorder by Lyketsos and Treisman,13 could be expressed
for depression after stroke as follows:
1. Under the appropriate circumstances, depression and stroke
occur together the great majority of the time. What is the
evidence pertaining to this criterion? Starkstein et al.14
reported that 7 of 8 patients (88%) with left-sided basal
ganglia lesions showed major depression, compared
with 1 of 7 patients (14%) with right-sided basal ganglia
lesions and 0 of 10 patients with thalamic lesions, either
right or left side. The patients were between 1 and 2
weeks post stroke. Among patients with cortical lesions,
Starkstein et al.15 found that 3 of 5 patients with left
anterior cortical lesions had major depression, compared with 0 of 9 patients with anterior or posterior right
hemisphere cortical lesions. These patients were also
studied between 1 to 2 weeks after stroke.
Astrom et al.16 found 12 of 14 patients (86%) with left
anterior lesions had major depression, compared with 2
of 7 (29%) with left posterior lesions and 2 of 23 (9%)
with right hemisphere lesions. These patients were also
studied 4 to 5 days after hospital admission. House et
al.17 found that 1 of 8 patients with left anterior lesions
and 0 of 5 patients with left posterior lesions had major
depression, compared with 0 of 7 with right anterior and
3 of 5 with right posterior lesions. These patients were
studied 1 month after stroke. Dam et al.,18 who studied
patients ranging from ,90 to .720 days after stroke, did

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not report the frequency of major depression with left
anterior lesions but found that depression scores were
higher in patients with right compared with left hemisphere stroke.
Morris et al.19 reported that 9 of 12 patients with left
prefrontal or left basal ganglia lesions had major or minor depression, compared with 1 of 12 (8%) with left
hemisphere lesions in other locations and 5 of 17 (29%)
with right hemisphere lesions. Patients were examined
approximately 8 weeks following stroke. Herrmann et
al.20 found that 8 of 14 patients (57%) with left anterior
lesions and aphasia had major (n45) or minor (n43)
depression, compared with 0 of 7 with fluent aphasia
and posterior left hemisphere lesions. These patients
were all less than 3 months post stroke. Thus, 4 of 6
groups studying independent samples of patients during the first few weeks to a few months after stroke
found significant associations of left anterior lesions
with depressive disorder. The later the patients were
studied after the acute stroke, the less likely investigators were to find this laterality phenomenon.
2. There is no other coherent explanation for the depression,
such as other illness, medications, substance use, or a personal
or family history of major depression. No study has demonstrated that major depressions following stroke may
be explained by concomitant physical illness, medications, or substance abuse. Morris et al.21 have demonstrated, however, that risk factors that would be expected to influence the expression of major depression
such as recent life events, premorbid personality vulnerability, impaired social function, and family history
of psychiatric disorderall appear to have additive effects on the likelihood of developing depression following stroke. Thus, the available data suggest that poststroke depressions, like primary depressive disorder,
may be multifactorial in cause and do not represent a
homogeneous population. These factors do not militate
against a causal relationship between stroke and depression but only identify that the risk of a strokes leading to depression increases with greater numbers of vulnerability factors.
3. The onset of depression is within one month of the stroke.
The discussion above pointed out that the association of
left anterior brain injury with poststroke depression
could not consistently be demonstrated after the first
few weeks following stroke. This finding provides support for the hypothesis of a causal relationship between
stroke and depression.
4. Resolution of the active phase of stroke is followed by resolution of depression in close temporal proximity. Because

JOURNAL OF NEUROPSYCHIATRY

stroke is a disorder that does not have a resolution, it is

difficult to be sure how to apply this criterion to poststroke depression. Numerous studies have demonstrated that major depression following stroke resolves
within the first year after stroke in the majority of
cases.1,17,22,23 One might conclude from these data that
major depression following stroke has a natural course,
usually less than 1 year. This does not argue either for
or against a casual connection between stroke and depression but only supports what is known about major
depression in other circumstances: that there is spontaneous remission in most cases.
5. There is specific evidence outside the clinical association to
indicate a pathophysiological mechanism through which the
stroke may cause depression. Apart from the association
of left anterior lesions with poststroke depression during the acute stroke period, probably the strongest evidence for a causal relationship between depression and
stroke is the clinicalpathological correlation between
the proximity of the lesion to the frontal pole and severity of depression. With the exception of the neuropathology of depression in Alzheimers disease, this
correlation of severity of depression with proximity of
the stroke lesion to the frontal pole is perhaps the most
consistently replicated clinicalpathological correlation
in psychiatry. Although the strength of the correlation
has varied from study to study and some investigators
have found correlations only in the left hemisphere
while others have found correlations in both the left and
right hemispheres, every investigator who has examined this relationship (even House et al.17) found that
the severity of depressive symptoms increased as the
lesion was closer to the frontal pole if patients were
studied within the first 6 months following stroke.20,22,24
There has been no other explanation besides a causal
connection of stroke and depression to explain this clinicalpathological correlation. This correlation has not
been explained, for example, by a relationship to a third
variable such as cognitive impairment, physical impairment, or aphasia. If Dr. House argues that there is no
causal relationship between stroke and depression, how
does he explain his own data showing that the location
of injury within the anterior-to-posterior axis correlates
significantly with severity of depressive symptoms as
measured by the Present State Examination score at 1
month after stroke and with both the Beck Depression
Inventory and the Present State Examination score at 6
months?
Other published data also suggest a basis for a causal
relationship between stroke and depression that involves the biologic changes brought on by the stroke
lesion. Several studies have demonstrated abnormalities

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of dexamethasone suppression in patients with poststroke major depression.2527 Barry and Dinan28 reported that patients with poststroke depression had a
blunted growth response to desipramine compared with
nondepressed stroke patients or normal control subjects.
This finding suggested subsensitivity of the alpha-2 adrenergic receptor as a basis for poststroke depression.
Bryer et al.29 found reductions in spinal fluid levels of
5-hydroxyindoleacetic acid in patients with poststroke
depression compared with nondepressed control subjects. Mayberg et al.30 demonstrated a significant correlation between the amount of serotonin S2 receptors in
the left temporal cortex and severity of depression in
patients with stroke. Taken together, these findings of
specific and potentially pathophysiological explanations for poststroke depression provide a very persuasive case for stroke and depression being causally related.

DIRECTIONS FOR FUTURE RESEARCH

We do not argue that depression after stroke is always
a specific complication of stroke. Rather, there are sufficient data to support the hypothesis that, in some circumstances, stroke causes depression through a pathophysiological process that may some day be identified
and specifically treated. Although House argues that
poststroke depression is no more than an understandable response to life-threatening physical illness, the cumulative data speak for themselves.
What is needed now is not an argument about
whether stroke can cause depression, but further study
of how to identify the patients who are most at risk,

what mechanism may mediate this depressive disorder,

and whether specific targeted treatments can be developed to ameliorate the depression as well as the associated increased mortality and delayed physical recovery that are associated with poststroke depression.3133
Future research addressing causal links of stroke to
other neuropsychiatric disorders (for example, anxiety
disorders) should also use operational criteria, such as
the ones proposed here, to assess causality between
stroke and these other disorders. It would also be important to assess the mechanisms of poststroke major
depression in patients without left anterior lesions and
whether these overlap with the depression provoked by
strategic lesion location.
Research should also examine whether stroke could
be used as a model to identify the risk factors and anatomical substrates of depression in other physical disorders, such as traumatic brain injury, multiple sclerosis,
epilepsy, Huntingtons disease, AIDS, and Parkinsons
disease, to mention only a few. Psychiatrists and neuroscientists have been working for many years to identify the structural and physiological basis of primary depressive disorder. Functional imaging studies30,34 have
frequently identified left prefrontal cortical abnormalities of metabolic activity in patients with primary depression. Structural imaging studies of depression in elderly patients have identified hyperintensities on MRI
scan in subcortical white matter and basal ganglia.35
These findings suggest overlap in the anatomic substrates of primary and poststroke depression. The insights that may be gained from studying patients with
symptomatic depressions may shed light on the pathophysiological mechanisms and anatomical substrates of
depressive disorder in patients without known neuropathology.

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