Lesion Location and Poststroke Depression : Systematic Review of the

Methodological Limitations in the Literature

Sanjit K. Bhogal, Robert Teasell, Norine Foley and Mark Speechley

Stroke 2004, 35:794-802: originally published online February 12, 2004

doi: 10.1161/01.STR.0000117237.98749.26
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 Lesion Location and Poststroke Depression
Systematic Review of the Methodological Limitations in the Literature
Sanjit K. Bhogal, BA(Hon); Robert Teasell, MD; Norine Foley, BASc; Mark Speechley, PhD

BackgroundIt has been hypothesized that poststroke depression (PSD) results from left hemisphere lesions. However,
attempts to systematically review the data investigating lesion location and PSD have yielded conflicting results. We
sought to investigate the methodological differences across the literature studying the relationship between lesion
location and PSD.
Summary of ReviewA MEDLINE literature search to retrieve articles investigating the association between PSD and
lesion location was performed. Information sought included source population of samples, definition of depression,
standardized measurement of stroke and depression, blinding, time since stroke onset, and study design. Odds ratios
(ORs) and 95% CIs were calculated with the use of Review Manager and MetaView statistical software. Twenty-six
original articles were reviewed. Much of the heterogeneity across studies reflected differences in methodology. The
direction of association between left hemisphere lesion location and PSD varied depending on whether patients were
sampled as inpatients (OR, 1.36; 95% CI, 1.05 to 1.76) or from the community (OR, 0.60; 95% CI, 0.39 to 0.92). Change
in the direction of association was also observed across assessment interval from the acute stroke (OR, 2.14; 95% CI,
1.50 to 3.04) to the chronic stroke (OR, 0.53; 95% CI, 0.30 to 0.93) phase. Differences in the measurement of
depression, study design, and presentations of results also may have contributed to the heterogeneity of the findings.
ConclusionsSeveral key initiatives should be addressed before future research is undertaken, including the development
of a comprehensive measure of PSD, optimal poststroke assessment intervals, and determination of a representative
population reference. (Stroke. 2004;35:794-802.)
Key Words: brain diseases cerebrovascular accident depression methods review literature

D epression is a common sequela of stroke. The preva-

lence 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 psycho-
logical 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 sug-
gesting 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.
However, this complex association is not well understood11
despite the large number of studies that have examined the
association. Recent attempts to systematically review studies
of lesion location and PSD have not served to clarify this
association. Pooling previous results, Robinson12 identified
specific relationships between the locations of brain injury
and the character and severity of poststroke mood distur-
bances. Robinson12 suggested that left anterior cerebral le-
sions were associated with significantly higher depression
scores than left posterior lesions. Diagnosable depressive
disorders were found in approximately 70% of stroke patients
with left frontal brain injuries. Robinson12 estimated that only
15% of the variance in depression could be explained by the
severity of intellectual impairment, physical impairment,
quality of social support, or age, whereas the site of the lesion
explained 50% of the variance.
In contrast, a systematic review by Carson et al13 found that
when data from 34 primary studies were pooled, lesion
location was not associated with depression. The pooled
relative risk of depression after a left hemisphere stroke,

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
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 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 of-
fered 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 un-
clear.15 Likewise, there is a lack of uniformity in the defini-
tion 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 hetero-
geneity 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 investi-
gated 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
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Lesion Location and Poststroke Depression 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 comput-
erized 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 measure-
ment of stroke, standardized measurement of depression, lesion
volume and lesion localization method, blind assessment of depres-
sion 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 Collabora-
tion Group. Differences in the frequency of depressed and nonde-
pressed 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 hemi-
sphere 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 hemi-
sphere 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.
796 Stroke March 2004

Articles Investigating Lesion Location and Poststroke Depression (n25)

Prevalence
Article of PSD, % Association Onset Since Stroke
28
Lipsey et al 34 Left hemisphere Within 2 weeks
Robinson et al1,7,24; Parikh et al25 47 Left hemisphere 3060 days
Sinyor et al10 23 Association changes over time 55 days
29
Collin et al 30 No association Undefined
Starkstein et al30 31 Left hemisphere 2 months
Starkstein et al31 42 Left basal ganglia 718 days
Starkstein et al32 Not given Association changes over time 35 days
33
Dam et al 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 Association changes over time 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
Iacoboni et al38 36 Association changes over time 7 days
39
Herrmann et al 22 Left basal ganglia Within 2 months
Morris et al40 24 Left basal ganglia 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 37.5 months on average
Nagaraja et al43 24 No association 2 weeks and 6 months
Pohjasvaara et al44 20 No association Within 3 weeks
MacHale et al45 50 Right hemisphere 6 months
46
Shimoda and Robinson Not given Association changes over time 3 months
Sato et al47 52 Association changes over time 2 weeks
Singh et al48 36 Association changes over time 3 months

and nondepressed patients with either left or right hemisphere
strokes.10,32,33,38,47
As shown in Figure 1, the 95% CIs for individual studies
were wide, and the test of heterogeneity was highly signifi-
cant (275.45, P0.00001), indicating substantial variation
in OR among studies. As noted earlier, much of this variation
is believed to reflect the methodological differences of the
literature. A review of the main methodological differences
that may contribute to heterogeneity across studies follows.
Source Populations and Study Samples
The source of patients was observed to vary across studies.
Patients were selected from 2 main sources: hospital-based
patients or community-based patients.22,23,29,34,35,42,47 The
population base of the study sample has been proposed by
some investigators15,48 to influence the outcome of the asso-
ciation between lesion location and PSD. When studies are
examined according to population source, 2 trends emerged
(Figure 2). Studies of hospital inpatients significantly favored
depression occurring after left hemisphere stroke (OR, 1.36;
95% CI, 1.05 to 1.76), whereas studies of community-based
samples were observed to significantly favor depression after
a right hemisphere stroke (OR, 0.60; 95% CI, 0.39 to 0.92).
References 7, 10, 26, 28, 30 33, 36 41, 44 46, 48.
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An interesting finding was that the test of heterogeneity
was significant across hospital inpatient studies (262.84,
P0.00001) but not across community-based studies
(21.62, P0.81). The significant heterogeneity across
hospital inpatient studies may reflect differences in the
composition of the study samples due to different healthcare
practices. For example, in Sweden 90% of all stroke patients
are admitted to the hospital; therefore, a hospital-based study
of stroke patients in this region is representative of most
stroke patients.36 However, in some regions fewer than half of
stroke patients are admitted at the time of acute episode.35
Patient characteristics also differed among studies. Several
samples were predominantly characterized by inner city
residence, low income, and black ethnicity, with approxi-
mately one half possessing less than a grade 9 educa-
tion.7,30,31,41,46 On the other hand, the patients of Singh et al14
were predominantly middle-class suburban residents, and
66% of the Sharpe et al34 sample was white.
Other inconsistencies in sample composition due to inclu-
sion criteria were also noted. Lipsey et al28 recorded patients
with a history of alcohol abuse and noted that more of these
patients were in the left hemisphere group than the right
hemisphere group (50% versus 17%). Similarly, inclusion of
patients with aphasia resulted in a higher percentage of
patients with communication disorders in the left hemisphere
 Bhogal et al
Figure 1. OR of poststroke depression after left hemisphere
stroke (n20).
stroke group than in the right hemisphere stroke group in 2
studies.39,46 In addition, 86% of the left hemisphere patients in
the study of Shimoda and Robinson46 had a family history of
psychiatric disorder. Alcohol abuse, family history of a
psychiatric disorder, and aphasia can increase the risk of
developing depression. The fact that these factors were
overrepresented in 1 group (ie, the left hemisphere stroke
group) may partly explain why a difference in the frequency
of depression between the 2 hemisphere groups was found in
these articles.
Definition, Diagnosis, and Standard Measurements
of Depression
Assessment of Depression
The timing and location of the assessment of depression were
well described in most articles. Most of the studies conducted
on hospital-based patients explicitly stated that patients were
interviewed for depressive symptoms in a private room,
between 11 AM and 2 PM, to minimize diurnal mood varia-
tion.7,26,28,30 32,37,38 Several studies assessed patients in their
residence, including their own homes or nursing
homes.22,23,34,35,42 Collin et al29 mailed out a questionnaire
regarding depressive symptoms to stroke patients living in the
community.
The most common measures used to assess the severity of
depression were the Hamilton Depression Rating Scale
(HDRS) and the Zung Self Report Depression Question-
naire.7,14,26,30 32 Lipsey et al28 calculated an overall depres-
sion score based on the Zung questionnaire and the HDRS,
whereas Dam et al33 used the HDRS in conjunction with the
Beck Depression Inventory (BDI). Other measures used to
assess the degree of depression were the BDI alone,35,42 the
Beck Hopelessness Scale,10 the Hopkins Symptom Check-
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Lesion Location and Poststroke Depression 797
list,10 the Composite Depression Index,10,40 the Cornell De-
pression Scales,39 the Montgomery-Asberg Depression Rat-
ing Scale,37,39,40,44,48 the Present State Examination,34 and the
Hospital Anxiety and Depression Scale.34 In total, 13 differ-
ent measures of depression were recorded in the 26 studies.
Depressive Symptoms
Diagnosing depression according to Diagnostic and Statisti-
cal 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 (DSM-
III-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-III-
R.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 incor-
rect. 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 Classifi-
cation of Diseases, 10th Revision criteria.
A concern with the use of the DSM criteria is that the
diagnostic criteria included vegetative symptoms of depres-
sion, 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 psychomet-
ric measures better capture patterns of depressive symptom-
ology 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
798 Stroke March 2004
specificity and poor predictive values because of their inclu-
sion 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 depres-
sion.51 It has been suggested that the discrepancies resulting
from sole use of self-report measures were due to underre-
porting 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.
Timing of First Interview After Stroke
Timing of first interview for depressive symptoms ranged
from the acute period7,22,30 32,36 41 to the subacute phase of
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Figure 2. OR of developing poststroke
depression after left hemisphere stroke
according to patient source (n19).
stroke rehabilitation23,35,44,45,48 to the chronic phase.34,42 One
study was noted to have staggered assessment times between
the acute and chronic stages of stroke.26
The time of assessment since stroke onset can potentially
influence study outcome. Patients interviewed during the
subacute phase may still be adjusting to their stroke experi-
ence, and depression in these patients may reflect this
transition stage. In fact, the highest rates of depression were
noted in patients assessed within the first 28 days of stroke
(Table).
When we examined studies that assessed depression within
the first 28 days of stroke, a significant association between
left hemisphere stroke and PSD was demonstrated (OR, 2.14;
95% CI, 1.50 to 3.04). However, studies that assessed
depression between 1 and 4 months observed that the asso-
ciation began to favor development of PSD after right
hemisphere stroke (OR, 0.93; 95% CI, 0.66 to 1.32), with a
significant association between right hemisphere stroke and
PSD at 6 months (OR, 0.53; 95% CI, 0.30 to 0.93) (Figure 3).
It is possible that the difference in association across the 3
time intervals reflects the degree of transient mood changes
related to the stroke event itself. Shimoda and Robinson46
suggested that impairments such as social isolation or visual
perceptual disorders associated with right hemisphere strokes
may play a role in the etiology of depression in the chronic
phases of stroke. Andersen et al22 suggested that this trend
may be reflective of the neuropsychological changes that may
 Bhogal et al
follow hemisphere strokes: catastrophic reaction with left
hemisphere strokes and denial and/or neglect or aprosody
with right hemisphere lesions. Accordingly, several
follow-up studies have suggested that PSD occurring in the
chronic phase may have a different mechanism than acute or
subacute PSD.10,32,36,38,46 48
Research Design: Cohort Versus Case-Control Study
Of the 25 studies reviewed, only 13 studies stated explicitly
how groups were assigned. Seven studies grouped patients
according to lesion characteristics, thereby using a cohort
design.1,22,30,31,36,41,45,48 Three studies33,36,40 used a case-
control design in which patients were sampled according to
depressive symptoms. Gainotti et al26 and Sato et al47 used a
cross-sectional design.
Knowledge of whether patients were grouped according to
lesion location or depression status is important to determine
the potential bias that may affect a study. For example, if
patients were grouped according to lesion characteristics,
then the findings might be biased as a result of patients with
lesions in certain stroke locations being probed more for
depressive symptoms or lack thereof. Grouping patients
according to their depressive symptoms runs the risk that the
radiologist reading the CT scan may be biased to look for
signs of lesions in one hemisphere or another.
The majority of studies ensured that the neurological
evaluators were blinded to the findings on psychopathologi-
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Lesion Location and Poststroke Depression 799
Figure 3. OR of developing poststroke
depression after left hemisphere stroke
according to time since stroke onset
(n17).
cal examination and that CT scans were read by an investi-
gator who was blinded to all clinical findings. Six studies
made no specific mention regarding blinding of asses-
sors.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 re-
viewed 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 per-
formed 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.
800 Stroke March 2004
2-tailed test the probability value becomes 0.09, which is
nonsignificant at the 0.05 level. Therefore, their alternate
hypothesis of unequal frequency of either major or minor
depression on the basis of left or right hemisphere lesion
location was not sustained according to a 2-tailed test. One
other study performed a 1-tailed test of significance.28
Adjustment for Multiple Comparisons
Another statistical error noted was the effect of multiple
comparisons on the level. Morris et al41 found no signifi-
cant association in the frequency of depression between right
and left hemisphere strokes. The authors then stratified on the
basis of size of lesion and performed multiple tests without
correcting for the number of comparisons. Robinson et al7
also performed multiple tests on their study sample without
correcting their level of significance. Only 2 studies14,42 used
a Bonferroni-adjusted level for multiple testing, and neither
study found a significant association between lesion location
and PSD.
Severity Versus Frequency
A common trend noted in the results was the tendency to
interchange the outcomes of severity of depression and
frequency of depression. Robinson et al7 indicated that left
hemisphere stroke patients had greater depression scores than
right hemisphere stroke patients as indicated on psychometric
scales, whereas the difference in frequency was not reported.
Similarly, Dam et al33 measured the severity of depression but
not the frequency of depression. Herrmann et al39 and
Angeleri et al42 also stated that the severity of depression was
greater in left versus right hemisphere lesions, but when
frequency of depression was examined, there was no differ-
ence between lesions involving the left or right hemisphere.
Use of Regression Models
Regression analysis was used in 3 studies. MacHale et al45
used stepwise regression to determine the predictive power of
lesion location on the development of PSD. Similarly, Sato et
al47 performed bivariate analyses with dummy variables used
to model lesion site, and the regression coefficient for each
variable was determined via stepwise regression. Singh et al48
used multiple linear rather than logistic regression modeling
because dichotomization of the depression variables was
arbitrary.
Inappropriate analysis and presentation of results contrib-
ute to the differences in the literature. Use of inappropriate
levels of significance misleads the readers. Moreover, the
interchanging use of severity of depression and frequency of
depression makes interpretation of results difficult. Finally,
the general absence of multiple regression models in the
literature suggests that the effects of confounding variables
were not removed from summary estimates of association
between lesion location and PSD.
Discussion
There were methodological differences across the PSD liter-
ature. 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
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location appeared to contribute to the development of PSD in
hospital inpatient population studies. Right hemisphere lesion
location appeared to contribute to the development of PSD in
community-based population studies. Differences in time
since stroke onset and the lack of a standard tool to assess
PSD also appeared to contribute to the heterogeneity of
findings. Furthermore, the inappropriate presentation of sta-
tistical analysis added to the limitations of the literature.
Even if the site and size of the brain lesion in stroke were
significantly correlated with depression, it is difficult to
determine whether depression is due to the clinical conse-
quences of stroke or due to neurophysiological changes that
may lead to depression. At present, it is not known whether
certain types or degrees of neurological impairment and
disability are associated with more or less depression.
The association of PSD and left hemisphere damage,
although compelling when the work of 1 group (the Johns
Hopkins group) is considered, has not been adequately or
consistently confirmed.15 The association between the site of
the stroke lesion and the likelihood of developing depression
independent of the clinical consequences remains unproven.
The authors decided to focus only on hemisphere lesion
location for simplicity since the methodological differences
that arose from hemisphere CT location were great. As a
result, the authors recognize that a limitation of this review is
that other lesion variables, such as anterior-posterior lesion
location, were not examined. It is possible that these variables
may also play a role in the development of PSD.
Before further research in this area is conducted, several
key initiatives should first be undertaken. These include the
following: development of an appropriate and standardized
measure of depression; identification of a representative
population source for research purposes; use of optimal time
since stroke onset to interview for PSD; and creation of more
comprehensive predictive causal models of PSD (as opposed
to investigation of lesion characteristics alone as a predictor
of PSD).
Development of an Appropriate and Standardized
Measure of Depression
A measure of depression that is best suited for the stroke
population is required. Such a measure would take into
account the functional, cognitive, and language impairments
that often accompany stroke. Furthermore, a measure of
depression for the stroke population must be sensitive to
some of the potential vegetative symptoms of the stroke itself
(psychomotor retardation, fatigue, and sleep and appetite
disturbances) that most conventional scales classify as de-
pressive symptoms.
Identification of a Representative Population Source
Given that the population source of a study can influence
results, the choice of entirely hospital-based samples or
entirely community-based samples will systematically skew
results. Accordingly, researchers should work together in
conducting large-scale studies that involve follow-up of all
stroke patients coming to emergency departments for treat-
ment, regardless of whether they were admitted to the
hospital or sent back to the community for treatment.
 Bhogal et al
Optimal Time After Stroke Onset to Interview
for PSD
Several authors have suggested that PSD over the long term
may have a different mechanism than acute or subacute PSD
with left-sided stroke and denial and/or neglect or aprosody
with right-sided lesions.10,32,37,46 48 Therefore, a prospective
cohort design would be best suited for studying the relation-
ship between lesion location and PSD. As patients are
followed, data regarding their recovery and present state
should be kept current.
Creation of Predictive Causal Models of PSD
Many of the studies reviewed investigated only the associa-
tion between lesion location and PSD. Further multifactorial
approaches were taken by only 3 studies.45,47,48 Given that
depression in the general population is multicausal, the study
of depression in the stroke population should be viewed as
such. On the basis of the research thus far, PSD should be
studied in terms of lesion location, functional impairment,
social dependence, intellectual impairment, and stroke onset.
Like other fields of psychiatry and psychology, the study of
PSD is riddled with methodological differences. An analysis
of these differences can be used to guide future research. One
such direction is the development of a depression measure for
the stroke population. Not only would such a measure allow
for accurate and reliable diagnosis of stroke for research
purposes, but it might also help clinicians to distinguish true
clinical depression from reactive adaptation in their patients.
In addition, the realization that depressive symptoms manifest
themselves differently during stroke recovery (acute versus
subacute versus chronic) and also across populations (hospi-
tal inpatient versus community) allows researchers and clini-
cians to approach the diagnosis and treatment of depression
accordingly. Finally, use of a multifactorial approach would
allow researchers to study several means by which different
stroke survivors can develop PSD. Such an approach can be
used to explain the variability in the frequency and severity of
PSD across populations and time. In addition, understanding
PSD in terms of causal complexes would allow clinicians to
monitor patients at risk of developing PSD.
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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