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epression is a common sequela of stroke. The prevalence of clinical depression varies from 20% to 50%
among inpatients during the acute and subacute phases of
recovery.1 Poststroke depression (PSD) has been reported to
negatively affect functional and cognitive recovery25 and is
associated with social withdrawal after stroke6,7 as well as
increased mortality.8
Two theories of PSD have been espoused. The first states
that depression after stroke or after brain injury is a psychological reaction to the clinical consequences of stroke. The
second suggests that depression arises as a consequence of
the specific brain lesion and presumably subsequent changes
in neurotransmitters. Accordingly, Folstein et al9 observed
that stroke patients suffered more from depression than
equally physically impaired orthopedic patients, thereby suggesting that the brain lesion itself could influence mood.
Furthermore, differences in emotional reactions depending on
hemisphere of the infarct suggested an organic basis of
PSD.10
The association between the location of brain lesion as a
result of stroke and PSD has been the topic of much research.
Received August 13, 2003; final revision received October 29, 2003; accepted November 25, 2003.
From the Department of Physical Medicine and Rehabilitation (S.K.B., R.T., N.F.) and Epidemiology and Biostatistics (M.S.), St. Josephs Health Care
London, Parkwood Hospital (S.K.B., R.T., N.F.), London, Ontario, Canada; and University of Western Ontario (S.K.B., R.T., N.F., M.S.), London,
Ontario, Canada.
Correspondence to Sanjit K. Bhogal, c/o Robert Teasell, MD, 801 Commissioners Rd E, London, Ontario N6C 5J1, Canada. E-mail
sanjit.bhogal@sjhc.london.on.ca
2004 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000117237.98749.26
794
Bhogal et al
compared with a right hemisphere stroke, was 0.93 (95% CI,
0.83 to 1.62). The authors noted that restricting the analyses
to higher-quality studies or major depressive disorders did
not affect their findings. Furthermore, the results were not
affected by stratification of time between stroke and the
assessment of depression. Thus, this systematic review offered no support for the hypothesis that the risk of depression
after stroke was influenced by lesion location.
A review conducted 2 years earlier did not yield definitive
conclusion concerning stroke lesion location and the risk of
depression.14 Singh et al14 systematically selected 26 original
articles that examined lesion location and PSD, of which 13
satisfied inclusion criteria. The authors noted that all of the
studies reviewed were methodologically flawed and were not
comparable with respect to sample, timing, and analysis of
CT scan and psychiatric evaluation. As a result, Singh et al14
did not believe that they could proceed with a formal
evaluation.
The inconsistent results among these 3 reviews (1 found an
association, 1 found no association, and 1 believed that the
studies could not be compared) indicate that there are
methodological problems in the PSD literature. There is a
lack of uniformity in the definition of stroke given the various
classifications of stroke that are used (eg, definition based on
clinical consideration versus category of stroke).15 When
stroke diagnostic criteria are unclear, data collection and
selection of appropriate samples for research are also unclear.15 Likewise, there is a lack of uniformity in the definition and measurement of depression.2 To further complicate
the issue, it is often difficult to differentiate endogenous
depression from an adjustment reaction to losses suffered
after the stroke event.15 Because of this last point, it is
difficult to separately test the 2 competing theories because
the assessment of the outcome will be confounded within and
between studies.15
Given the inconsistent results across the 3 aforementioned
reviews and the methodological concerns regarding research
in PSD,14,15 in this article we review and critique the research
methodology used in studies investigating the relationship
between stroke lesion location and depression. Although
Carson et al13 (2000) examined the relative risk of developing
PSD according to time since stroke onset and source of
patients, this article provides a more thorough methodological
review of the literature in an attempt to explain the heterogeneity of results across the literature. In addition, key
research initiatives within the area of PSD are proposed.
Areas of interest include the sample population source,
definitions of stroke and depression, imaging used, timing of
diagnosis, and statistical analysis.
Methods
Study Identification and Selection
Two MEDLINE literature searches (via PubMed) were used to
identify all studies from January 1970 to March 2003 that investigated the association between stroke lesion location and depression.
Search limits included English, human, middle age: 45. The first
search included the key words depression, cerebrovascular accident
or stroke, computerized tomography or CT scan, and post stroke and
the combined exploded key words depression AND cerebrovascular
accident OR stroke AND computerized tomography OR CT scan
795
AND post stroke. The second search included the key words
depression, cerebrovascular accident or stroke, and computerized
tomography or CT scan and the combined exploded key words
depression AND cerebrovascular accident OR stroke AND computerized tomography OR CT scan.
Articles identified in the MEDLINE searches were included if the
purpose was to study the association between stroke lesion and the
development of PSD. Studies were limited to stroke survivors and
excluded studies that included nonstroke patients.
Eleven articles were retrieved from the first search, of which 1 was
a review article and 5 met inclusion criteria. The second search
yielded 34 articles, of which 2 were review articles, 3 were
duplicates from the previous search, and 18 met inclusion criteria.
Studies cited in the retrieved articles but not identified through the
MEDLINE literature search were sought, bringing the total number
of primary articles retrieved to 38.
Data Abstraction
A single reviewer extracted data from the selected studies onto a data
abstraction form. Information sought included sample population,
definition of stroke, definition of depression, standardized measurement of stroke, standardized measurement of depression, lesion
volume and lesion localization method, blind assessment of depression to CT scan and vice versa, timing, and final conclusions.
Statistical Analysis
For articles that did not report odds ratios (ORs) and/or CIs,
frequency of patients with and without depression and site affected
were recorded from the articles; the Peto OR and 95% CI were
calculated with the use of Review Manager and MetaView, a
statistical software package available from the Cochrane Collaboration Group. Differences in the frequency of depressed and nondepressed patients between left and right hemisphere strokes were
assessed by the 2 statistic with Yates correction with the use of
Statcalc, a statistical software package available through the Centers
for Disease Control. Fishers exact test was used when observed cell
counts were 5. Statistical significance was set at the 0.05 level.
Results
A total of 38 articles were retrieved. Seven articles were
excluded because they did not meet inclusion criteria.9,16 21
In 2 instances, multiple articles reported different analyses
performed on a single group of patients (References 1, 7, 24,
25 and References 26, 27). In the end, 26 original reports
were included in the review (Table).10,22 48
Ten articles observed no significant association between
lesion locations and the frequency or severity of PSD.* Two
studies cited a significant association between right hemisphere strokes and PSD33,45; 4 studies noted a significant
association between left hemisphere strokes and PSD7,28,30,41;
3 studies noted greater depression associated with left hemisphere basal ganglia lesions31,39,40; and 7 studies noted
changes in the association between lesion location and PSD
over time.10,32,36,38,46 48
Given that many studies did not provide ORs and/or
corresponding CIs, the present article calculated the OR of
developing PSD for a left hemisphere stroke (Figure 1). ORs
and/or CIs could not be calculated for all studies because of
insufficient detail in the reports of the findings. One study did
not provide the number of nondepressed patients who had
suffered either a left or right hemisphere stroke.42 Five studies
did not provide frequency counts of the number of depressed
*References 22, 23, 26, 29, 34, 35, 37, 42 44.
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Articles Investigating Lesion Location and Poststroke Depression (n25)
Article
Lipsey et al
28
Prevalence
of PSD, %
Association
34
Left hemisphere
Within 2 weeks
47
Left hemisphere
3060 days
Sinyor et al10
23
55 days
Collin et al
29
Starkstein et al30
30
No association
Undefined
31
Left hemisphere
2 months
Starkstein et al31
42
718 days
Starkstein et al32
Not given
35 days
Dam et al
33
30
Right hemisphere
23 weeks
Sharpe et al34
18
No association
45 days
House et al35
20
No association
1 month
Astrom et al36
25
35 years
Agrell et al37
29
No association
Undefined
Andersen et al22
Not given
No association
Within 7 days
Burvill et al23
Not given
No association
4 months
36
7 days
Herrmann et al
22
Within 2 months
Morris et al40
24
Within 1 month
Morris et al41
34
Left hemisphere
710 days
Angeleri et al42
29.7
No association
Within 10 days
Gainotti et al26,27
42.5
No association
Nagaraja et al43
24
No association
Pohjasvaara et al44
20
No association
Within 3 weeks
MacHale et al45
50
Right hemisphere
6 months
3 months
Iacoboni et al38
39
46
Not given
Sato et al47
52
2 weeks
Singh et al48
36
3 months
Bhogal et al
797
list,10 the Composite Depression Index,10,40 the Cornell Depression Scales,39 the Montgomery-Asberg Depression Rating Scale,37,39,40,44,48 the Present State Examination,34 and the
Hospital Anxiety and Depression Scale.34 In total, 13 different measures of depression were recorded in the 26 studies.
Depressive Symptoms
Diagnosing depression according to Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria was the most
common approach. Several studies diagnosed depression on
the basis of Diagnostic and Statistical Manual of Mental
Disorders, Third Edition (DSM-III) symptom criteria for
major depression and minor depression as elicited by a
modified Present State Examination.7,22,23,30 32,35,46 Nagaraja
et al43 used the HDRS to determine Diagnostic and Statistical
Manual of Mental Disorders, Revised Third Edition (DSMIII-R) diagnoses. In some cases, clinical judgment was
required to translate responses to the appropriate DSM-III
symptom criteria.
strom et al36 diagnosed depression according to the
DSM-III symptom criteria with physical disorder (stroke) on
axis III, while several studies used the DSM-III-R with the use
of a structured clinical interview designed for the DSM-IIIR.34,37,39 41,44 One study used the more recent Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV) with the Schedule for Affective Disorders and
Schizophrenia.45
Gainotti et al26 used the DSM-III-R diagnostic criteria with
the Visual Analogue Dysphoria Scale to elicit responses from
patients suffering from aphasia. The inclusion of a measure to
assess depression in patients with aphasia is unfortunately
overlooked by many studies. Primeau15 noted that because the
DSM-III criteria rely heavily on verbal responses, assessment
of these patients with the DSM-III criteria may not be
feasible, and interpretation of their responses may be incorrect. Gainotti et al26 noted that when assessment of patients
with aphasia took their communication deficit into account,
left hemisphere lesions were not a major determinant of PSD.
It has been proposed that diagnosing stroke patients with
the use of the DSM-III-R is inappropriate because depression
may be a consequence of the brain lesion per se, with
stroke-induced changes in neurotransmitter concentration in
the cerebrum.15,26 For this reason, several studies opted to
move away from DSM criteria and based diagnosis of
depression on other criteria. Two studies used the Centre for
Epidemiological StudiesDepression,41,47 2 used the Rome
Criteria for Depression,33,38 and Angeleri et al42 clinically
assessed depression using International Statistical Classification of Diseases, 10th Revision criteria.
A concern with the use of the DSM criteria is that the
diagnostic criteria included vegetative symptoms of depression, such as psychomotor retardation, fatigue, and sleep and
appetite disturbances, which may be a consequence of the
stroke event itself independent of affect.49 While psychometric measures better capture patterns of depressive symptomology and are better able to chart changes in depressive
symptomology in response to treatment, their sensitivity has
not been fully studied.49 Goldberg50 (as cited by Primeau et
al,15 1988) reported that self-report measures tend to have low
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March 2004
specificity and poor predictive values because of their inclusion of somatic symptoms.
There has been considerable debate regarding the use of
self-report measures to diagnose and measure depression,
given the known incongruity between DSM-III diagnostic
criteria and psychometric measures.51 Dam et al33 observed
significantly higher degrees of depression in patients with
right hemisphere stroke when measured by the HDRS;
however, this difference disappeared when the BDI was used.
Dam et al33 suggested that this was caused by indifference to
the symptoms that are often seen in patients with right
hemisphere lesions. This neglect would be more pronounced
in self-rating than in an interviewer-scored scale. Gordon et
al51 noted that the HDRS alone was more congruent with the
DSM-III than were self-report measures. The combination of
self-report measures (eg, the Zung scale) with the HDRS
resulted in a discrepancy with DSM-III diagnosis of depression.51 It has been suggested that the discrepancies resulting
from sole use of self-report measures were due to underreporting of depressive symptomology compared with observer
rating.51 Gordon et al51 interpreted the findings to suggest that
either patients tend to minimize the severity of their mood
disorders or examiners are sensitive to patients behaviors.
Bhogal et al
799
cal examination and that CT scans were read by an investigator who was blinded to all clinical findings. Six studies
made no specific mention regarding blinding of assessors.28,33,37,40,42,44 Although blinding of both the radiologist
and psychiatrist helps to reduce interview and detection bias,
in the case of the psychiatrist, the clinical presentation (eg,
side of hemiparesis) of a stroke patient provides clues
regarding the location of the stroke. A solution would be to
ensure that all assessors involved are unaware of the studys
hypotheses and prediction. Unfortunately, none of the reviewed studies indicated whether the assessors were unaware
of the purpose of the study.
Presentation of Results
Level of Statistical Significance
Eight of the studies indicated that all analyses were performed as 2-tailed tests at the 0.05 level.34 37,39,42,45,48 The
importance of stating whether a test was performed as a
1-tailed versus 2-tailed test was highlighted by the results of
Starkstein et al,30 who did not state whether they tested
significance at a 1-tailed or 2-tailed level. A reanalysis of
their findings using a 1-tailed test demonstrated a significant
association (Yates2.78, P0.044), a result very similar to
that presented by Starkstein et al.30 However, with the
References 7, 22, 23, 26, 30 32, 34, 35, 38, 45, 46, 48.
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Discussion
There were methodological differences across the PSD literature. These differences contribute to the discrepant findings
in the association between lesion location and PSD. Much of
the heterogeneity noted across the studies appeared to be a
function of the population source. Left hemisphere lesion
Bhogal et al
Acknowledgments
This study was supported by a grant from the Ministry of Health and
Long-Term Care of Ontario, Heart and Stroke Foundation of
Ontario, and Canadian Stroke Network.
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