Drugs Aging (2012) 29:793-806

DOI 10.1007/S40266-012-0012-5
F SYSTEMATIC REVIEW
Effect of Selective Serotonin Reuptake Inhibitors in Alzheimer's
Disease with Comorbid Depression
A Meta-Analysis of Depression and Cognitive Outcomes
Amir A. Sepehry Philip E. Lee Ging Yuek R. Hsiung
B. Lynn Beattie Claudia Jacova
Published online: 11 October 2012
Springer International Publishing Switzerland 2012
Abstract
Background Comorbid depression is a leading neuro-
psychiatrie complication in the Alzheimer's disease (AD)
syndrome. In 2011, diagnostic criteria for AD were revised
to include neuropsychiatrie symptoms. It has been pro-
posed that adding an antidepressant to existing treatment
for AD could provide relief for not only depressive but also
cognitive symptoms.
Objective The aim was to quantitatively review published
studies to examine the efficacy of selective serotonin
reuptake inhibitor (SSRI)/serotonin-noradrenaline (norepi-
nephrine) reuptake inhibitor (SNRI) therapy for alleviation of
comorbid, diagnosed depression as well as cognitive decline
in AD.
Methods A search of electronic databases was performed.
Studies were retained for analysis if SSRI/SNRI antide-
pressant therapy was compared with placebo among AD
patients with comorbid depression. Effect-size (ES)
estimates (Hedges' g) were calculated using Comprehen-
sive Meta-Analysis software.
Results From 598 examined studies, 12 SSRI studies met
the inclusion criteria, and from these, only six met all cri-
teria, among which five reported sufficient and consistent
data to be included in the meta-analysis. Within a random
effect model, ES estimates of the first and second nested
global analyses were non-significant, non-heterogeneous
and small to null at the endpoint for depression, favouring
SSRIs, -0.06 and -0.10, respectively {p > 0.05). The ES
for global cognition as measured by the Mini-Mental State
Examination was negligible (ES = 0.001).
Conclusions Current evidence does not support the effi-
cacy of SSRI treatment for symptoms of comorbid
depression in AD. However, studies differed in terms of
criteria for diagnosis of depression, the compound tested
and outcome measures for depression. These factors could
account for the lack of a clear benefit for depression.
A. A. Sepehry G. Y. R. Hsiung C. Jacova
University of British Columbia (UBC),
College for Interdisciplinary Studies, Graduate Program
in Neuroscience, Vancouver, BC, Canada
A. A. Sepehry P. E. Lee G. Y. R. Hsiung C. Jacova (E3)
UBC Division of Neurology, Department of Medicine,
UBC Hospital, 2211 Wesbrook Mall, Rm 152,
Vancouver, BC V6T 2B5, Canada
e-mail: cjacova@mail.ubc.ca
A. A. Sepehry P. E. Lee G. Y. R. Hsiung
B. L. Beattie C. Jacova
Clinic for Alzheimer Disease and Related Disorders,
UBC Hospital, Vancouver, BC, Canada
P. E. Lee B. L. Beattie
UBC Division of Geriatric Medicine, Department of Medicine,
Vancouver, BC, Canada
1 Introduction
Alzheimer's Disease (AD) is one of the leading public
health concerns in the 21st century, and has been estimated
to account for 63 % of all dementias [1, 2]. Alzheimer's
Disease International, the international federation of
Alzheimer associations, estimated that 36 million people
worldwide are living with dementia, with numbers dou-
bling every 20 years, leading to 66 million by 2030 and
115 million by 2050 [3]. These estimates are consistent
with current projections for AD provided in Canadian and
US reports, in which the number of individuals affected by
AD is projected to increase dramatically in the next two
decades, when there will be 1 million affected individuals
by 2038 in Canada [1] and 7.7 million by 2030 in the USA
\ Adis
794 A. A. Sepehry et al.
[4]. In this setting, any therapeutic intervention capable of
providing some benefit warrants close scrutiny.
1.1 Alzheimer's Disease (AD) and Comorbid
Depression
Depression in AD is a disabling condition that is under-
recognized and highly correlated with increased healthcare
utilization, risk of suicide, and greater severity and accel-
eration of cognitive impairment [5-10]. The reported
prevalence of comorbid depression or depressive symp-
toms in individuals with AD has been quite variable,
ranging from 3 to 50 % [11], likely due to differences in
methods of assessment, diagnostic criteria, stages of
dementia, and other factors. Comorbid depression com-
plicates diagnosis, affects treatment approaches and out-
comes, and decreases the quality of life of affected
individuals as well as their caregivers.
1.2 Pharmacotherapy for AD and Depression
Pharmacological treatment of AD is currently based on two
internationally approved types of medications: cholines-
terase inhibitors (ChEIs) and the A^-methyl-D-aspartate
(NMDA) receptor agonist (memantine). These classes of
medications are prescribed either alone or in combination
[12]. Pharmacotherapeutic guidelines for treating depres-
sion in AD recommend that a pharmacological treatment
with minimal and least severe adverse effects be used as a
first-line approach [13, 14]. The treatments of choice are
selective serotonin reuptake inhibitors (SSRIs), including
fiuoxetine, paroxetine and sertraline; serotonin-noradren-
aline (norepinephrine) reuptake inhibitors (SNRIs),
including venlafaxine; or other newer agents, including
mirtazapine. The recommendation issued by the Canadian
Consensus Conference on Dementia (3rd CCCDTD) [15] is
that if a person with dementia and depression has an
inadequate response to non-pharmacological interventions,
a trial of antidepressant treatment should be considered,
with preference given to an SSRI. Additionally, a recent
European guideline by the British Psychological Society
and The Royal College of Psychiatrists, commissioned by
the National Institute for Health and Clinical Excellence
(NICE) and the Social Care Institute for Excellence (SCIE)
(NICE-SCIE), recommends that people with dementia who
also have major depressive disorder should be offered
antidepressant medication, and that compounds with anti-
cholinergic effects should be avoided. They recommend
that treatment should be started by clinicians with specialist
training, who should follow the NICE-SCIE clinical
guideline 'Depression: Management of Depression in Pri-
mary and Secondary Care' after a careful risk-benefit
assessment [16].
Evidence has accrued since the 1980s [17-19] that
suggests that when individuals experiencing cognitive
impairment and comorbid depression are treated with
antidepressant medication, depressive symptoms may
improve while cognitive symptoms may not. Currently, the
primary treatment goal in AD is to improve function by
alleviating cognitive and behavioural symptoms. A sec-
ondary treatment goal is to minimize factors exacerbating
cognitive impairment and hindering the efficacy of
antidementia drugs and other interventions. Thus, recognizing
and treating depression symptoms in order to maximize
function appears an important step. There may be also a
neurobiological rationale. Emerging evidence from animal
studies suggests that antidepressant treatment may have neu-
roprotective and anti-infiammatory properties [20-22].
No review or meta-analysis focused specifically on AD
with comorbid depression; nor did any explicitly focus on
both depression and cognition as pre-specified outcomes of
the meta-analysis. Hence, using a meta-analytic approach on
study-level data, we intended to (1) systematically review
the currently available evidence examining the use of SSRI
or SNRI mono-therapy to alleviate comorbid depression as
well as cognitive symptoms in patients with AD with a
concurrent diagnosis of depression; and (2) highlight gaps in
the literature, which warrant further research into evidence-
based pharmaco-therapeutic approaches in AD.
2 Methods
2.1 Data Sources, Searches and Selection
We conducted a search of the electronic search engines
[PubMed, EMBASE, Cumulative Index to Nursing and
Allied Health Literature (CINHAL), Cochrane Central
Register of Controlled Trials (CENTRAL) and PsycINFO]
on 30 January 2011, without any language restrictions.
PubMed was searched using the terms (a) "second and
third generation antidepressants OR citalopram OR dul-
oxetine OR escitalopram OR fiuoxetine OR fiuvoxamine
OR nefazodone OR paroxetine OR sertraline OR venla-
faxine" AND (b) "cognitive OR cognition OR neuropsy-
chology OR neuropsychological" AND (c) "Alzheimer's
OR Alzheimer's disease OR AD OR Alzheimer". Psy-
cINFO on the OVID platform was searched differently in
order to collect the maximum number of studies. Search
terms were "second and third generation antidepressant" as
major word or major subject headings OR "citalopram OR
duloxetine OR escitalopram OR fluoxetine OR fiuvox-
amine OR nefazodone OR paroxetine OR sertraline OR
venlafaxine" AND "Alzheimer". Cross-referencing was
carried out with the aid of several reviews and an earlier
meta-analysis of the efficacy and safety of antidepressant
AAdis
SSRIs in AD for Depression and Gognition
795
use for depression in AD [23]. The search was updated on
30 July 2011, with one new study emerging that met our
criteria. Agents not classifiable as an SSRI or SNRI were
excluded from our investigation. Additionally, the search
was substantiated a posteriori on April 2012 by examining
web addresses with clinical trials registrations (http://
clinicaltrials.gov/) and ALOIS (http://www.medicine.ox.ac.
uk/alois/). Using the antidepressant intervention with AD
as the health status/diagnosis provided only one ongoing
study (ESAD/NCT00702780) that partially met our selec-
tion criteria. In this trial, diagnosis of depression at onset
was not specified; hence, the trial was not added to the
search results.
Studies were evaluated based on a set of selected a priori
inclusion and exclusion criteria. Initially abstracts were
examined for explicit inclusion criteria. Subsequently, in
order to achieve a high standard and minimum heteroge-
neity, studies were examined on the basis of a set of
exclusion criteria (Table 1). After two authors (A.A.S. and
P.E.L.) had independently coded the studies, the kappa
measure of agreement was calculated to ensure consistency
in coding (k = 1.00 [100 % consistency was reached]).
Furthermore, where appropriate, the authors of the studies
were contacted for raw or continuous data.
Power analysis with G*Power (Version 3; Faul, Erdf-
elder, Lang and Buchner, Dsseldorf, Germany) [24] was
carried out a priori in order to have an estimate of the
number of studies needed to calculate an omnibus Hedges'
g effect-size (ES) estimate. Several sets of analyses were
performed. For all analyses, the alpha level was set to 0.05,
two tails. One analysis was done for medium-small ES and
one for small ES. After setting the power to 0.8 and ES to
0.4, the estimated unequal sample size ratio of 1.3:1 was 88
for the control group and 114 for the treatment group.
Alternatively, when setting the power level to 0.8 and ES to
0.2, the estimated unequal sample size (1.3:1) was 349 for
the control group and 453 for the treatment group.
Comprehensive Meta-Analysis (CMA) (Version 2;
Biostat Inc., Englewood, NJ, USA) [25] was used to cal-
culate ES estimates and examine for publication bias.
Where appropriate, within a random effect model, omnibus
ES estimates were derived with Hedges' g [26], providing
an unbiased ES adjusted for sample size. Expecting vari-
ability in ES estimates, a random effect model that toler-
ated population level inferences and is more stringent than
a fixed effect model was prominently used across our meta-
analytic examination [27].
In the presence of heterogeneity, examination of the
moderating factors using Cochran's Q Chi-square test and f
was accomplished [28]. A significant Q-test value suggests
rejection of the homogeneity hypothesis of the effect set; the
f statistic [= 100 % X (g - df)/Q] that shows quantifica-
tion of heterogeneity in the degree of inconsistency (total
Table 1 Selection criteria for studies
Inclusion criteria
1. Presence of individuals suffering from AD
2. Presence of depression as a comorbid condition
3. Prescription of any novel antidepressant
Exclusion criteria
1. Did not report on geriatric population with AD
2. Reported on mild cognitive impairment
3. Did not investigate pharmacological treatment (was not a
clinical trial) or was a head-to-head study without a placebo
arm
4. Depression was an exclusion criterion, there was no diagnosis
for depression, or depression was non-concomitant to AD
5. Failed to include cognitive assessment as an outcome measure
6. The study design was of low quality according to Jadad et al.
[72], such as a case report, case series, case study, letter or
commentary or editorial without data
7. Was a review or meta-analysis
8. Exclusively investigated pharmacological markers or genetic
markers, or was an animal study
9. Included research participants with other diagnosis such as
OCD, or comorbid alcoholism, and third diagnosis, or
diagnosis was mixed with medical illnesses
10. Investigated antidepressant treatment approach for smoking
cessation
AD Alzheimer's disease, OCD obsessive-compulsive disorder
variation across studies that is due to heterogeneity rather
than chance) was used. Values for this statistic range from 0
and 100 %, where low, moderate and high f values are 25,
50 and 75 %, respectively. A value of 0 % denotes the
absence of heterogeneity, and larger values show increased
heterogeneity [28].
Calculation of the post hoc fixed ES estimate for endpoint
baseline difference was accomplished using the DSTAT
(Version 1; Lawrence Erlbaum Associates Inc., Hillsdale,
NJ, USA) [29]. In the absence of continuous descriptive
measures (mean, SD), study authors were contacted to
retrieve the appropriate statistics. Alternatively, given dis-
tributional assumptions, in the absence of the mean and SD,
data from the median and inter-quartile ranges were trans-
formed to mean and SD. Overall, our meta-analysis was
consistent with the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) statement [30].
3 Results
3.1 Characteristics of the Included Trials
After removing duplicates, we identified 598 studies, col-
lected from search engine hits (Fig. 1). After evaluation for
inclusion and exclusion criterion, 12 studies were included
A Adis
796 A. A. Sepehry et al.
598 abstracts identified through database
12 studies matched inclusion and
exclusion criteria
5 were investigating mixed dementia
168 were reviews, meta-analyses and surveys
6 were commentaries, guidelines, letters or book
chapters
10 were experimental non-human studies (animal, post-
mortem and molecular investigation)
39 were case studies
3 were missing cognitive testing as an outcome measure
4 were missing a placebo arm
93 failed to show diagnosis of depression or a
depression scale, or depression was excluded
258 were studying a diagnosis other than AD
1 was investigating benzodiazepines
1
5 studies were explicitly
reporting on the same
study (DIADS-1); only
the most recent study
was included
1
3 studies explicitly
reported on the same
study (DIADS-2); only
1 was included in the
examination
V
1
6 studies included in meta-
analytic examination
298 patients enrolled
with SSRI
antidepressant
323 patients
enrolled for
placebo treatment
A total of 621 enrolled
individuals in trials
Fig. 1 Flowchart showing study exclusion and inclusion. AD Alzheimer's disease, SSRI selective serotonin reuptake inhibitor
in this preliminary investigation of SSRI antidepressant use
for treatment of depression complicating AD. No studies of
SNRI antidepressant treatment met our criteria. Hence, we
limit our meta-analysis and discussion to SSRIs in the
remainder of this paper. There were no studies in non-
English language that met our criteria. Certain studies
explicitly reported on the same trials, e.g. Depression in
Alzheimer's Disease Study 1 (DIADS-1) and DIADS-2
[31-36]. Hence, only the most recent studies with the most
comprehensive outcome data were included [31, 34, 36].
However, other DIADS-1 and DIADS-2 published
manuscripts were used for additional information on
demographics and methods when needed. Accordingly, we
identified six studies (A' = 4 + 1 + 1) for our meta-analysis:
four studies excluding DIADS-1 or -2, one describing
DIADS-1 and one describing DIADS-2 (Fig. 1). The total
number of patients enrolled in SSRI treatment arms from
those studies was 297, and the total number of patients
enrolled in placebo arms was 318. These sample sizes
support the minimum 1.3:1 ratio needed to run a meta-
analysis and calculate an omnibus estimate for a medium-
small ES.
Study sample sizes (treatment and placebo) ranged from
31 to 228 patients. The majority of the patients enrolled in
the studies were female (67 %), and one study included
only females for both arms of the study [37]. The largest
attrition was observed in the Health Technology Assess-
ment Study of the use of Antidepressants for Depression in
A Adis
SSRIs in AD for Depression and Cognition 797
Table 2 Descriptive representation of the
Study, year
Magai et al., 2000 [37]
Petracca et al., 2001 [44]
DIADS-1 [31-33, 35]
Rozzini et al., 2010 [45]
DIADS-2 [34, 36]''
Banerjee et al., 2011 [38]
Patients
TX
17
17
24
66
67
107
studies for ag
(n)
PL
14
24
20
90
64
111
;e, sex, study attrition and
Female (%)
TX
100
47
83
81
59.7
68
PL
100
71
50
71
48.4
64
sample included
Age [y, mean
TX
88.4(6.1)
70.2 (6.3)
75.5 (9.5)
75.7 (7.6)
76.5 (8.0)
80 (8.4)
(SD)]
PL
90.1 (6.5)
71.3 (6.9)
79.9 (5.2)
75.9 (7.2)
78.2 (8.0)
79 (8.8)
Attrition (i
TX
12
17
25"
NR
10.9
26
PL
14
12
12.5"
NR
7.5
36.5
NR not reported, PL placebo, TX treatment
^ Based on the attrition reported on page 493 of the Munro et al. [74]
'' Attrition is calculated based on the CSDD data as provided by the authors
Dementia (HTA-SADD) in the treatment arm with sertra-
line [38]. The average age for treatment arms ranged from
70.2 to 88.4 years, and for placebo arms it ranged from
71.3 to 90.1 years. Overall, patients enrolled in the placebo
arms of the studies were older than those in the treatment
arms (Table 2).
As shown in Table 3, the included studies reported both
longitudinal change scores and endpoint data. Five studies
were double-blind, placebo-controlled trials. Four of these
were randomized. One trial was observational. The average
duration of the trials was 21.3 weeks when we included the
Mini-Mental State Examination (MMSB) data from the
DIADS-2 at 24 weeks, and 19.3 weeks when we included
Cornell Scale for Depression in Dementia (CSDD) data
from the DIADS-2 at 12 weeks, with a range between
6 weeks and approximately 9 months. Five of six studies
explicitly report a diagnosis of probable AD according to
the National Institute of Neurological and Communicative
Disorders and Stroke and the Alzheimer's Disease and
Related Disorders Association (NINCDS-ADRDA) criteria
[39]. Three of the six included studies explicitly reported
diagnoses of depression based upon Diagnostic and Sta-
tistical Manual of Mental Disorders, Fourth Edition (DSM-
IV) criteria, whereas others used different, yet inconsistent
approaches, where the method utilized was not explicitly
reported or, for example, the provisional diagnostic criteria
for depression in AD were utilized [40]. All studies
included mixed types of depression (e.g. minor and major
depression). Sertraline was the most frequently prescribed
SSRI antidepressant (N = 4 studies, plus an additional
study with mixed SSRIs). Other SSRIs included fluoxetine,
or a mix including citalopram, escitalopram and paroxe-
tine. All studies incorporated a dose titration. Concurrent
treatment, allowing multiple and existing pharmacological
treatments, was reported by three studies. One non-
randomized trial and two randomized controlled trials
explicitly stated that they allowed the use of ChEIs with
SSRIs, and two studies explicitly reported excluding
patients with other concomitant treatment; however, one
study did not report on allowing poly pharmacy. MMSE
[41] was the most administered tool to assess cognition
(A' = 5). The CSDD (also abbreviated as CS) [42] and
Hamilton Depression Scale (HAM-D) [43] were the most
frequently utilized depression scales, used in four and two
trials, respectively (Table 4). The presence of a minimum
of three studies using the same cognitive scale (MMSE) or
depression scale (CSDD) allowed us to run a meta-analytic
examination of the evidence and to maintain high homo-
geneity with respect to outcome measures between studies.
3.2 Analysis of the Studies via Comprehensive Meta-
Analysis
3.2.1 Depression
An initial global nested analysis using CMA was per-
formed including all depression scales and counting each
study once. Given that the DIADS-1 study reported on two
depression scales (CSDD and HAM-D), two global nested
analyses including each scale once were performed. The
first global nested analysis included DIADS-1 (Lyketsos
et al. [31] 2003) with only the HAM-D results, and gen-
erated an ES estimate for global depression of 0.06
(p = 0.54; A^ = 5; = 4.94; df=4;p = 0.29; f = 19.08)
(Fig. 2). Then the second global nested analysis was carried
out, replacing the CSDD with the HAM-D from the same
study, resulting in ES = -0. 10; p ^ 0.40; A^ = 5;
Q = 3.n;df= A;p = 0.53;/^ = 0.01 (Fig. 3). The sample
sizes for the global nested analysis were treatment = 184, and
placebo =191. Both effects were small, non-significant and
homogeneous.
Subsequent efficacy analyses were carried out separately
for studies reporting on CSDD (A^ = 4) (Fig. 4) and those
reporting on HAM-D (A' = 2) (Fig. 5). Analysis of CSDD
A Adis
798 A. A. Sepehry et al.
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A Adis
SSRIs in AD for Depression and Cognition 799
Table 4 Cognitive and depression outcome measurement
Study, year BIC (AD severity) Cognition Depression
Magai et al., 2000 [37]
Petracca et al., 2001 [44]
DIADS-I [31-33, 35]
Rozzini et al., 2010 [45]
DIADS-2 [34, 36]' ' ' '
Banetjee et al., 2011 [38]''
NR (late-stage)
MMSE >10 (NR)
MMSE >10 (NR)
NR (mild to moderate)
MMSE 10-26 (mild to moderate)
NR (NR)
Knit-brow face; sad face
MMSE
MMSE; EOWPVT-R; HVLT-R;
Rivermead; WISC-R
MMSE; ADAS-Cog
MMSE
MMSE
CS; GS
HAM-D
CSDD; HAM-D
MMSE mean change GDS
CSDD
CSDD
AD Alzheimer's disease, ADAS-Cog Alzheimer's Disease Assessment Scale-Cognitive subscale, BIC Baseline Inclusion Cognitive Criteria, CS
Cornell Scale for Depression, CSDD Cornell Scale for Depression in Dementia, EOWPVT-R Expressive One-Word Picture Vocabulary Test-
Revised, GDS Geriatric Depression Scale, GS Gestalt Depression Scale, HAM-D Hamilton Depression Scale, HVLT-R Hopkins Verbal Learning
Test-Revised, MMSE Mini-Mental State Examination, NR not reported, WISC-R Wechsler Intelligence Scale for Children-Revised
^ Authors were contacted in order to obtain relevant continuous data (P. Rosenberg and L.T. Drye, personal communication)
'' CSDD data is from 12 weeks, MMSE data is from 24 weeks
'^ Authors were contacted in order to obtain relevant continuous data (S. Banetjee and J. Hellier, personal commutiication)
Hedges' g and 95 % Cl
Fiuoxetine
Sertraline
Sertraline
Sertraline
Sertraline
Model
Random
Study name
Petracca et al. 2001
Lyketsos et ai. 2003
Banerjee et ai. 2011
Magai et al. 2000
Rosenberg et al. 2010
Outcome
HAM-D
HAM-D
CSDD
CSDD
CSDD
Time
point
End
End
End
End
End
Statistics for each study
Hedges'
9
-0.126
-0.498
0.000
-0.257
0.083
-0.062
Variance
0.112
0.091
0.027
0.142
0.033
0.011
Lower
iimit
-0.781
-1.090
-0.320
-0.996
-0.274
-0.264
Upper
limit
0.529
0.094
0.320
0.482
0.441
0.139
p vaiue
0.706
0.099
1.000
0.496
0.648
0.544
Sample size
Treatment
15
24
68
15
62
Piacebo
20
20
82
12
57
-2.00 -1.00 0.00 1.00 2.00
Fig. 2 First nested analysis; effect-size estimate for depression [Hamilton Depression Scale (HAM-D) and Cornell Scale for Depression in
Dementia (CSDD)] for endpoints; each study was considered once (N = 5) [31, 34, 37, 38, 44]
Model Study name
Petracca et al. 2001
Lyketsos et al. 2003
Banerjee et ai. 2011
Magai et ai. 2000
Rosenberg et al. 2010
Random
Outcome
HAM-D
CSDD
CSDD
CSDD
CSDD
Time
point
End
End
End
End
End
Statistics
Hedges'
g
-0.126
-0.665
0.000
-0.257
0.083
-0.102
for each study
Lower
Variance iimit
0.112
0.093
0.027
0.142
0.033
0.014
-0.781
-1.264
-0.320
-0.996
-0.274
-0.337
Upper
limit
0.529
-0.066
0.320
0.482
0.441
0.133
p value
0.706
0.030
1.000
0.496
0.648
0.396
Sampie size
Treatmeni
15
24
68
15
62
: Piacebo
20
20
82
12
57
Hedges' g and 95 % CI
Fiuoxetine
Sertraiine
Sertraiine
Sertraiine
Sertraiine
-2.00 -1.00 0.00 1.00
Fig. 3 Second nested analysis; effect-size estimate for depression [Hamilton Depression Scale (HAM-D) and Cornell Scale for Depression in
Dementia (CSDD)] for endpoints; each study was considered once (Af = 5) [31, 34, 37, 38, 44]
data, comparing treatment arm with placebo arm at end-
point, yielded an unbiased non-significant Hedges' g [42]
favouring treatment, using a random effect model (ES =
-0. 12; p = 0.42; N = 4: placebo n = 171, treatment
n 169). These results were mildly heterogeneous
(Q = 4.94; df=3;p = 0.18; f = 39.05), and the largest
included study [38] accounted for 44 % of the fixed
relative weight in the ES estimate. For HAM-D data, using
the fixed effect model, a non-significant Hedges' g of 0.33
favouring treatment with SSRIs was found for the limited
number of studies using the HAM-D {N 2: placebo
n = 40, treatment n 39). There was no difference
between fixed and random effect models. This estimate
falls between small and medium size according to Cohen's
A Adis
800 A. A. Sepehry et al.
Model
Fixed
Random
Fixed
Random
Group by
time point
Baseline
Baseline
Baseiine
Baseiine
Baseiine
Baseiine
End
End
End
End
End
End
Study name
Banerjee et al. 2011
Lyketsos et ai. 2003
Magai et ai. 2000
Rosenberg et ai. 2010
Banerjee et ai. 2011
Lyketsos et ai. 2003
Magai et ai. 2000
Rosenberg et al. 2010
Outcome
CSDD
CSDD
CSDD
CSDD
CSDD
CSDD
CSDD
CSDD
Statistics for each study
Hedges'
g
-0.178
0.428
-0.184
0.053
-0.043
-0.021
0.000
-0.665
^0.257
0.083
-0.075
-0.121
Variance
0.018
0.090
0.142
0.030
0.009
0.014
0.027
0.093
0.142
0.033
0.012
0.022
Lower
limit
-0.443
-0.161
-0.921
-0.288
-0233
-0.254
-0.320
-1.264
-0.996
-0.274
-0.287
-0.414
Upper
lin^it
0.087
1.018
0.554
0.393
0.148
0.213
0.320
-0.006
0.482
0.441
0.137
0.172
p value
0.189
0.155
0.625
0.762
0.659
0.862
1.000
0.030
0.496
0.648
0.487
0.417
Sample size
Treatment
107
24
15
67
68
24
15
62
Piacebo
111
20
12
64
82
20
12
57
Hedges' g and 95 % Gl
-1.00 -0.50 0.00 0.50 1.00
Fig. 4 Gross-sectional comparison of treatment arm and placebo (depression): favours treatment with selective serotonin reuptake inhibitors
[Cornell Scale for Depression in Dementia (CSDD)] (/V = 4) [31, 34, 37, 38]
Hedges' g and 95 % CI Model
Fixed
Random
Fixed
Random
Group by
time point
Baseline
Baseline
Baseline
Baseline
End
End
End
End
Study name
Petracca et al. 2001
Lyketsos et ai. 2003
Petracca et al. 2001
Lyketsos et ai. 2003
Outcome
HAM-D
HAM-D
HAM-D
HAM-D
Time point
Baseline
Baseline
End
End
Statistics for each study
Hedges'
9
-0.447
0.307
-0.050
-0.063
-0.126
-0.498
-0.331
-0.331
Variance
0.099
0.089
0.047
0.142
0.112
0.091
0.050
0.050
Lower
iimit
-1.063
-0.279
-0.475
-0.802
-0.781
-1.090
-0.770
-0.770
Upper
limit
0.170
0.894
0.375
0.676
0.529
0.094
0.108
0.108
p vaiue
0.156
0.304
0.816
0.867
0.706
0.099
0.140
0.140
-2.00 -1.00 0.00 1.00 2.00
Fig. s Cross-sectional comparison of treatment arm and placebo (depression), favours treatment with selective serotonin reuptake inhibitors
[Hamilton Depression Scale (HAM-D)] (A^ = 2) [31, 44]
guidelines, and it was homogeneous (Q 0.68; df\;
p = 0.41; f = 0.01) (Figs. 4 and 5).
3.2.2 Cognition
An analysis of the studies reporting assessment of global
cognition with MMSE (JV = 5) [31, 36, 38, 44, 45] and
assessment of depression with HAM-D (N = 2) [31, 44]
was conducted. A non-significant Hedges' g (ES 0.001;
p = 0.99) was found for MMSE completers (treatment
= 196; placebo n = 222; z = O.Ol; p = 0.99, two-tail)
(Fig. 6), and the largest study accounted for 36.58 % of
the fixed relative weight [38]. The -statistic value for
MMSE was non-significant (Q = 1.58; df = 4; p = O.Sl;
f 0.01). There was no difference in ES estimates
between fixed and random effect models, suggesting very
little variability among the included studies. However,
because of the small number of studies included in each
analysis, ranging from two to five studies, Q-statistics may
not have had sufficient power to detect significant hetero-
geneity, even if this was present. Examination of the funnel
plot (not shown) of studies included in the cognition
analysis suggests possible study bias given that the studies
are distributed asymmetrically and that the smaller studies
are at the bottom of the plot on only one side of the mean.
Complying with the PRISMA statement, further examina-
tion with classic fail-safe N (which addresses the concern
that the observed significance may be spurious) was carried
out. Data from five studies reporting MMSE results yielded
a z value of 0.05 with the corresponding two-tailed
p value of 0.96. Given that the combined result was not
statistically significant, the fail-safe N was not considered
to be relevant (Fig. 6).
Of the studies with CSDD data, only two also reported
MMSE results. Our ES estimate based on a random effect
model at the endpoint was non-significant and favouring
A Adis
SSRIs in AD for Depression and Cognition 801
Model Group by Study name Outcome Time point Statistics for each study
Fixed
Random
Fixed
Random
time point
Baseiine
Baseline
Baseline
Baseline
Baseline
Baseline
Baseline
End
End
End
End
End
End
End
Petraccaetal.2001
Lyketsos et al. 2003
Rozzini et al. 2010
Banerjee et al. 2011
Weintraubetal. 2010
Petracca et al. 2001
Lyketsos et al. 2003
Rozzini et al. 2010
Banerjee et al. 2011
Weintraubetal. 2010
MMSE
MMSE
MMSE
MMSE
MMSE
MMSE
MMSE
MMSE
MMSE
MMSE
Baseline
Baseline
Baseline
Baseline
Baseline
End
End
End
End
End
Hedges'
9
0.000
0.180
0.000
0.039
0.248
0.088
0.088
-0.044
-0.087
0.079
-0.166
0.159
0.001
0.001
Variance
0.097
0.089
0.026
0.025
0.030
0.007
0.007
0.111
0.088
0.026
0.036
0.053
0.010
0.010
, Lower
limit
-0.609
-0.404
-0.316
-0.268
-0.094
-0.081
-0.081
-0.698
-0.670
-0.237
-0.540
-0.293
-0.191
-0.191
Upper
limit
0.609
0.764
0.316
0.347
0.590
0.258
0.258
0.610
0.496
0.395
0.207
0.611
0.192
0.192
p value
1.000
0.545
1.000
0.802
0.156
0.308
0.308
0.895
0.770
0.625
0.383
0.490
0.995
0.995
Hedges' g and 95 % CI
-1.00 -0.50 0.00 0.50
Fig. 6 Effect-size estimate comparing treatment arm of the studies to placebo (cognition), favouring placebo (N = 5). [31, 36, 38, 44, 45]
MMSE Mini-Mental State Examination
placebo (ES = -0. 14; p = 0.37; 95 % CI = -0.46, 0.17)
(refer to Table 4 for included studies).
3.2.3 Post Hoc Analysis
Given the lack of significant ES estimates for depression
and cognition, moderating factors were not fully examined.
However, we conducted further analyses (a) on the baseline
data, examining for sampling bias; (b) on the possibility of
generating a global neurocognitive index and on factors
specific to the clinical validity of treatment, such as global
functional outcome and quality of life; (c) on the difference
from baseline to endpoint for the placebo group; and (d) on
adverse events.
The ES estimate obtained from comparing treatment and
placebo groups at baseline suggests that there were no
sampling biases in the included studies; the ESs were small
in size (HAM-D: ES = -0. 06; CSDD: ES = -0.02;
MMSE: ES = 0.09). The comparison of baseline to the
endpoint for the placebo arm showed no significant
difference for MMSE (ES = -0. 03; p = 0.76; 95 % CI
-0. 24, 0.18; r= -0.02) but a significant difference for
CSDD (ES = 0.98; /? = 0.001; 95% CI 0.77, 1.19;
r = 0.44).
A global neurocognitive ES index based on all the
reported neuropsychological tests with the exclusion of
MMSE or functional outcome measures (e.g. Activities of
Daily Living) was not feasible given that only one study
reported on neuropsychological tests at endpoint: DIADS-1
[31, 33].
The examination of the endpoint global functional out-
come from the DIADS-1 study with the Psychogeriatric
Dependency Rating Scale-Activities of Daily Living
(PGDRS-ADL), the DIADS-2 study with the Alzheimer's
Disease Cooperative Study (ADCS)-Activity of Daily
Living Scale, and the HTA-SADD study with Bristol
Activities of Daily Living-Activity Limitation (BADL-AL)
showed that globally either there was no significant dif-
ference or very little difference exists between sertraline
groups and placebo at the end of the trials. As to quality of
life, HTA-SADD and DIADS-2 were the only studies to
report on such outcome measures, and both investigating
groups reported non-significant differences between treat-
ment and placebo arms.
The number of patients in the placebo arm administered
the MMSE at baseline was 194, and at the endpoint, the
number was 166, which is a 14 % loss. The number of
patients in the placebo arm administered the CSDD at
baseline was 207, and at the endpoint, the number was 171,
which is roughly a 17 % loss. In the treatment arm, the
percentage loss was higher: MMSE (baseline = 253;
endpoint = 196) 22.5 % loss; CSDD (baseline = 213;
endpoint = 169) 20.7 % loss. Non-parametric examination
for this variation was not possible given that the emerging
sample for MMSE differed from that for CSDD.
An overview of the adverse events for the included
studies with a single SSRI (fluoxetine or sertraline), but not
mixed SSRIs, showed that fluoxetine was better tolerated,
with few drop-outs and few reported adverse events (e.g.
mild confusional state in only one patient) [44], in contrast
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802 A. A. Sepehry et al.
to sertraline, for which adverse events were frequent [31,
36-38]. Banerjee et al. [38] reported the largest list of
adverse events for both SSRI and placebo treatment (86 vs.
58, respectively). As for the only non-controlled study
(Rozzini et al. [45]), since multiple SSRIs were used and
the study was observational, no conclusion can be drawn
with regard to adverse events. This notwithstanding, we
included every eligible study to avoid the file-drawer effect
[46].
4 Discussion
Using a systematic meta-analytic approach, we evaluated
the currently available evidence regarding SSRI and SNRI
mono-therapy for the treatment of depressive and cognitive
symptoms in AD patients with concurrent depression. We
did not find any SNRI trials meeting our selection criteria
and limited our analysis to SSRIs. Notwithstanding power
limitations, we found non-significant effects in two
depression nested analyses including CSDD and HAM-D,
and found no effects on a measure of global cognition, the
MMSE. There was a suggestion that the size of the effect
for CSDD (very small) and HAM-D (small to medium) was
different. Compared with previous work, the external
validity of our analysis is stronger because we have
(a) included the largest clinical trial published to date on
the topic and (b) we have included trials from the UK, Italy
and the USA. Based on these findings, support for the use
of SSRIs as a class of medications for the treatment of AD
with concurrent depression appears quite weak. However,
several caveats are in order. Firstly, we cannot rule out that
within the class, different SSRI compounds may have
different effects in AD given their unique pharmacological
properties. For example, fiuoxetine has antagonistic prop-
erties at serotonin 5-HT2c receptors, which could increase
norepinephrine and dopamine neurotransmission [47]. The
majority of trials to date, including HTT-SADD, have
examined sertraline, and only a few have addressed other
antidepressants. Secondly, there is no gold standard diag-
nostic approach to depression in AD. The studies included
in these analyses have either utilized DSM-IV criteria or
other approaches such as the Olin provisional approach,
which requires fewer symptoms for a diagnosis of
depression [10]. Because of statistical constraints, and the
lack of a significant ES estimate, we have not conducted
analyses on moderating factors but cannot exclude the
possibility that outcomes may be moderated by how
depression is diagnosed in AD. Finally, there is no gold
standard outcome measure for depression in AD. In the
studies included in this work, two scales have been uti-
lized: the CSDD and the HAM-D. It is possible, and in fact
somewhat supported by our data, that the effect of SSRI
treatment is scale dependent. The HAM-D places strong
emphasis on neurovgtative signs, and it is possible that
these rather than mood symptoms benefit from SSRI
treatment. However, we cannot further assess this possi-
bility without patient-level data on specific neurovgtative
symptoms, such as sleep impairment.
4.1 Comparison to Other Meta-analyses and Reviews
There have been previous meta-analytic studies that have
either examined the efficacy and safety of a variety of
antidepressants for treatment of depression in AD, includ-
ing tricyclic antidepressants, despite recent guidelines
discouraging their use [14], or the effect of antidepressants
from a limited number of placebo-controlled trials in
people with depression in dementia, with inconclusive
results [23, 48]. In these studies, broad inclusion criteria
were used for the diagnosis of depression. Additionally,
reviews of treatment of depression in AD showed limita-
tions [49, 50], particularly in the methodological approach,
such that no clear conclusion can be drawn. For example, a
2010 review of the pathophysiology, diagnosis and treat-
ment approach for depression in AD included seven ran-
domized placebo-controlled trials, from which data from
DIADS-1 were utilized twice, with inclusion of both data
from an earlier paper and the final trial paper [49]. How-
ever, the authors concluded that the data were too sparse to
fully assess the benefit-risk ratio of antidepressants for
managing depression in AD or other dementias. Another
review examined the full spectrum of antidepressants and
concluded that further data are needed to assess the benefits
and risks of antidepressant therapy in patients with
dementia [50]. In this study, no degree of cognitive benefit
was assessed in relation to the improvement in symptoms
or signs of depression. Furthermore, this study was not
specific to AD. Thus the cumulative evidence on efficacy
of SSRI treatment in AD for depressive and cognitive
symptoms remains inconclusive.
In contrast to the conclusions of reviews, a meta-analysis
of ten studies on the effect of second-generation (SSRIs,
SNRIs and other classes but not tricyclics) antidepressant
therapy for late-life depression found that antidepressants
were more effective than placebo in elderly depressed
individuals, with methodological and statistical heteroge-
neity [51]. We did not find evidence of such treatment
benefits in subjects with AD. However, we also encountered
heterogeneity, both in the depression outcomes that were
used and in the ES estimate for one outcome (CSDD). In
contrast to other meta-analyses and reviews, following the
PRISMA statement, we used very specific inclusion criteria,
and focused only on studies addressing SSRI therapy for
depression in AD, and not on the entire dementia spectrum.
Additionally, we were able to include the largest and most
A Adis
SSRIs in AD for Depression and Cognition
803
recently published (2011) antidepressant trial, thus reaching
significant sample size and power to systematically exam-
ine treatment effects. We also found that there is no ran-
domized placebo-controlled clinical trial explicitly
investigating the effect of a ChEI with concomitant SSRI or
SNRI on cognitive symptoms and diagnosed comorbid
depression as per our selection criteria.
4.2 Measurement Scales in AD with Concurrent
Depression
We noted dissimilarities in the outcome scales that have
been utilized. The CSDD is an interview-based assessment
tool that collects information about the signs and symptoms
of depression in dementia from informants and patients
during the past week. In contrast, the patient-based HAM-
D rates change, frequency and intensity of diagnosed
depression with regard to treatment outcome. It is possible
that the latter scale is more sensitive to small changes in
depressive symptoms. It is beyond the scope of our work to
evaluate these scales, but it should be kept in mind that
interpretation of scores on scales relying on self-report in
subjects with AD, comorbid depression and MMSE scores
of <20 is difficult because self-report may not be valid
[52]. The studies using the HAM-D differed from those
using the CSDD on other methodological dimensions also.
Firstly, all studies using CSDD as the outcome measure
examined sertraline, whereas the two studies using HAM-
D utilized fluoxetine and sertraline. Secondly, the CSDD
ES estimate is based on larger sample sizes, with one large
study (HTA-SADD) accounting substantially for the
CSDD ES estimate. It is important to note that there was
heterogeneity in the CSDD ES estimate, which may be due
to methodological differences in the trials, sample size
differences, variation in AD symptom severity, or the
approach to diagnosis of depression (DSM vs. Ohn criteria
or other). Examination of these factors was not possible but
will be needed to draw definitive conclusions with respect
to SSRI efficacy in AD with concurrent depression.
4.3 Selective Serotonin Reuptake Inhibitors
and Cognition
It is clear that the MMSE is an imperfect tool for measuring
progression in cognitive decline because of its low sensi-
tivity to change in less than moderate dementia severity,
such as in our sample [53-55], and its large measurement
error, which can be as large as the mean annual change
[56]. The evidence to date suggests that there is a lack of
traditional neuropsychological assessment as an outcome
measure in studies of SSRIs in AD. The use of a com-
prehensive battery of neuropsychological tests sensitive to
the impact of depression would be warranted [57, 58], with
particular emphasis on psychomotor speed and uid intel-
ligence. In fact, cognitive declines including slower reac-
tion time and dysexecutive symptoms as a result of
depression have been consistently reported in non-demen-
ted individuals [59, 60]. These measures might yield a
pattern of improvement associated with SSRI treatment in
AD. On a different note, given the stage of the disease,
caregiver impression of cognitive function or behavioural
symptoms may be an important outcome measure to
understand the impact of these compounds.
4.4 Strengths and Limitations
An important strength of our study is that we examined the
treatment of depression in a well-defined clinical entity,
focusing exclusively on dementia due to AD, with a
diagnosis of comorbid depression. It is conceivable that
depression is experienced differently in different dementias
and along the continuum of cognitive change from mild
cognitive impairment to AD [61]. For example, the results
of the largest sertraline clinical trial prompted the authors
to speculate that the neurobiology of depression in AD may
be different from that of depression without dementia [38].
Hence, it is also possible that response to SSRIs differs
among these entities. Another strength of this study is that
we have provided higher methodological quality by meet-
ing the PRISMA consensus statement.
There are limitations to our study. First, few studies
were included in the analyses for depression, and these
were done separately for HAM-D {N = 2) and for CSDD
(N = 4). We opted to stratify by outcome measure and
sacrificed some degree of methodological rigor in this
process. Second, we have included all possible studies
[randomized controlled trials and non-randomized studies
(e.g. including Rozzini et al. [45]) equally] in the omnibus
ES estimate. This may not be a problem given that we have
no significant fail-safe N result to report. Third, the result
may not generalize to AD patients newly diagnosed on the
basis of the 2011 recommendations from the National
Institute on Aging and the Alzheimer's Association
working group, given that the revised criteria highlight
partial inclusion of behavioural impairment as one of the
features in all-cause dementia [62]. Fourth, we have
included data from different times for the DIADS-2 study,
in that we have data for the MMSE from both baseline and
at 24 weeks [36], and for CSDD from baseline and at
12 weeks [34]. Although, we have not counted the DIADS-
2 trial twice in the analysis, this limitation renders con-
clusions regarding change of cognition as a result of
change in depressive symptoms difficult. Furthermore, the
DIADS-2 trial reported that specific depression subtypes
(such as major or minor depression) have no relation to
treatment outcome [63]. Here we have opted not to run a
A Adis
804 A. A. Sepehry et al.
sub-analysis considering depression subtypes as a moder-
ating factor given the lack of significant heterogeneity and
the limitations of the data reported in the individual trials.
4.5 The Big Picture and Areas for Future Investigation
This meta-analysis uncovered factors that necessitate fur-
ther investigation in relation to depression in AD. What
appears to matter is how depressive symptoms are diag-
nosed and assessed. From the neurobiological perspective,
depression could be a symptom of AD, a disorder in its
own right, or both. Clinical presentation of depression
overlaps with AD, and this is reflected in the DSM-IV
criteria for major depression (mood, psychomotor activity,
cognition and vegetative symptoms). For now, clinicians
need to adopt an in-depth phenomenological approach to
ascertain a diagnosis of depressive disorder.
A point of importance is the significant improvement on
depression scales in the placebo arm as assessed by CSDD.
It is possible, though not proven, that being in an antide-
pressant trial may be by itself an effective approach. This
speculation, of course, will need careful study to gather
support for this hypothesis. We concur with the conclusion
by the HTA-SADD group [38] that sertraline may not be a
good fit as a first-line antidepressant, and that psychosocial
approaches may be more effective for treating depression
in AD. However, we noted in our meta-analysis that ser-
traline was the compound most frequently studied and
other compounds utilized in clinical care did not undergo
the same amount of scrutiny. Therefore, conclusions can-
not be drawn at present specifically on the efficacy of the
latter. Furthermore, other classes of antidepressants, such
as SNRIs, are commonly prescribed to persons with AD,
yet the efficacy and safety of these medications have not
been formally assessed.
We agree that depression in dementia is likely different
from depression in aging, and that its treatment or assess-
ment cannot be extrapolated from treatment approaches in
normal elderly. Furthermore, consistent with a recent
review for management of neuropsychiatrie symptoms
associated with AD by Gauthier et al. [64], the literature
remains very limited, such that no clear inferences can be
drawn or suggestions made to change the current clinical
guideline for treating comorbid depression in AD using
SSRIs. Hence, we conclude that depression in AD is still
not a well-understood phenomenon. Until more is known
and given the revised criteria for AD dementia [62], which
include behavioural changes, there are myriad opportuni-
ties to explore this important clinical phenomenon with
regard to treatment effectiveness and the components of
diagnosis.
5 Conclusions
Current evidence does not support the efficacy of SSRI
treatment for symptoms of comorbid depression in AD.
However, there is substantial variation in individuals'
clinical response and tolerance even within the same class
of medication. A real necessity for antidepressant treatment
must be established, and criteria for application should be
developed at an individual patient level [65]. There is a
lack of consensus with regard to the diagnostic approach
and outcomes in trials of antidepressants in AD. When a
harmonized diagnostic approach exists, trials adopting this
approach may yield more reliable outcomes. Additionally,
clinicians, in evaluating the benefits of antidepressant
treatment, should consider the possibility of improved
quality of life and increased functional independence [66-
68]. Potential risks, including injurious falls [69], exacer-
bation of suicidal ideation and possible abnormal changes
in the electrical activity of the heart [70], should not be
underestimated. In addition, follow-up monitoring for
possible metabolic abnormalities (e.g. hyponatraemia)
should be taken into consideration [71 ]. In summary, SSRIs
for AD patients with coexisting depression should be pre-
scribed with caution.
Acknowledgments The authors wish to express their gratitude for
the provision of unpublished trial data upon request from Dr. Sube
Banerjee and Jennifer Hellier on behalf of the HTA-SADD group, and
from Drs. Paul B. Rosenberg and Lea T. Drye on behalf of the
DIADS-2 group.
Funding and Conflicts of Interest The author have no conflicts of
interest to report. Amir A. Sepehry, PhD candidate, is funded by the
Canadian Institutes of Health Research (CIHR) (Frederick Banting
and Charles Best Canada Graduate ScholarshipsDoctoral Awards).
Dr. Lee has received funding from the Cullen Family, St. Paul's
Hospital Foundation and has received honoraria for speaking and
participating in advisory boards for Janssen-Ortho, Novartis and
Pfizer. Dr. Lee is a co-investigator in the Alzheimer Drug Therapy
Initiative (ADTI) project, funded by the British Columbia (BC)
Ministry of Health Services, and is a co-investigator for the clinical
trials at the University of British Columbia Hospital (UBCH) Clinic
for Alzheimer's Disease and Related Disorders (CARD), funded by
Baxter, Bristol-Myers-Squibb, Elan, Janssen, Pfizer, Hoffman-La
Roche, and Genentech. Dr. Hsiung is supported by a Clinical
Genetics Investigatorship award from the CIHR, and has received
research support from Baxter, Bristol-Myers-Squibb, Elan, Janssen,
Pfizer, Hoffman-La Roche, and Genentech at the UBCH-CARD.
Dr. Beanie is a co-investigator for the clinical trials at the UBCH-
CARD, funded by Baxter, Bristol-Myers-Squibb, Elan, Janssen,
Pfizer, Hoffman-La Roche, and Genentech. She is also receiving grant
funding from the CIHR and from the ADTI, which is funded by the
BC Ministry of Health Services. Dr. Jacova receives funding from the
CIHR and the BC Ministry of Health Services through the ADTI.
Drs. Lee, Hsiung and Jacova gratefully acknowledge support from the
Ralph Fisher Professorship in Alzheimer's (Alzheimer Society of
British Columbia).
A Adis
SSRIs in AD for Depression and Cognition 805
Individual Contributions to the Manuscript Amir A. Sepehry
designed and conducted data collection, coding, statistical analysis
and interpretation of the data, and was involved in writing of
the various drafts of the manuscript. Dr. Lee was the second rater in
the evaluation of studies for inclusion in the meta-analysis; wrote the
discussion section; and revised the manuscript. Dr. Hsiung had input
into various sections of the manuscript and was involved in overall
revisions. Dr. Beaitie had input into various sections of the manu-
script and was involved in overall revisions and editing for content.
Dr. Jacova supervised the project and interpretation of the data,
revised the manuscript and edited for content.
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