Research

International Journal of Stroke

0(0) 1–7
Effects of SSRI exposure on hemorrhagic ! 2017 World Stroke Organization
Reprints and permissions:
complications and outcome following sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/1747493017743055

thrombolysis in ischemic stroke journals.sagepub.com/home/wso

Schellen Christoph, Ferrari Julia, Lang Wilfried and

Sykora Marek; on behalf of the VISTA Collaborators1,*

Abstract
Background: Selective serotonin reuptake inhibitors (SSRI) may interfere with platelet function, and pre-stroke SSRI
treatment has been associated with increased hematoma volumes and mortality in hemorrhagic stroke patients. The
effects of SSRI on the risk of hemorrhagic complications after thrombolysis in ischemic stroke patients are unclear.
Aims: To examine the effects of pre-stroke SSRI exposure on bleeding complications, functional outcome, and mortality
following thrombolysis in ischemic stroke.
Methods: Data including standard demographic and clinical variables as well as baseline and follow-up stroke severity
(measured by National Institutes of Health Stroke Score), functional outcome (measured by modified Rankin Scale) at 3
months, and mortality at 7 and 90 days were extracted from the Virtual International Stroke Trials Archive. Multivariable
binary logistic regression was used for statistical analyses.
Results: Out of 1114 ischemic stroke patients treated with recombinant tissue-type plasminogen activator, 135 (12.1%)
had previous SSRI exposure. Symptomatic intracranial hemorrhage occurred in 30 (2.7%) patients. Of those, 2 (1.5%,
n ¼ 135) were in the SSRI pretreatment group and 28 (2.9%, n ¼ 979) were SSRI naive patients. Pre-stroke SSRI exposure
in thrombolysed patients showed association with neither bleeding complications (P ¼.58) nor functional outcome
(P ¼.38) nor mortality (P ¼.65).
Conclusions: Results from this large retrospective ad hoc database cohort study indicate that pre-stroke SSRI exposure
in ischemic stroke patients who receive thrombolytic treatment is not associated with bleeding complications, functional
outcome, or mortality.

Keywords
Stroke, SSRI, thrombolysis, outcome, intracerebral hemorrhage, mortality

Received: 26 June 2017; accepted: 5 August 2017

with oral anticoagulant treatment.1 Pre-stroke treat-

Introduction
Selective serotonin reuptake inhibitors (SSRI) are
among the most commonly prescribed classes of
medications.1–3 Their broad therapeutic effect for a
multitude of psychiatric disorders and their safe side
effect profile have made them a first choice agent of
many clinicians3 and multiple studies have reported
beneficial effects of SSRI treatment in ischemic stroke
patients.4–11 On the other hand, SSRI use has been
associated with bleeding complications in the gastro-
intestinal system and intracranially due to the inhib-
ition of platelet serotonin reuptake and consequently
reduced platelet function.3 Previous investigations
have shown that SSRI exposure increases the risk of
intracerebral bleeding, in particular when combined
ment with SSRI has been linked to increased hematoma
volumes and mortality in patients with hemorrhagic
stroke, but showed no association with mortality in
the general ischemic stroke population.5 The effects of
SSRI pretreatment on bleeding complications after
thrombolysis for ischemic stroke are currently unclear.
Department of Neurology, St. John’s Hospital, Medical Faculty, Sigmund
Freud University Vienna, Vienna, Austria
*
A list of all VISTA collaborators is given in the Acknowledgments.
Corresponding author:
Christoph Schellen, Department of Neurology, St. John’s Hospital,
Johannes-von-Gott-Platz 1, Vienna 1020, Austria.
Email: christoph@schellen.at

International Journal of Stroke, 0(0)

2 International Journal of Stroke 0(0)
Hypothesis
In this study, we hypothesized that pre-stroke SSRI
exposure in patients receiving recombinant tissue-type
plasminogen activator (rt-PA) is associated with an
increased risk of thrombolysis-related bleeding compli-
cations, unfavorable functional outcome, and increased
mortality.
Methods
Data source and processing
Data from ischemic stroke patients comprising stand-
ard demographic and clinical variables were extracted
from the Virtual International Stroke Trials Archive
(VISTA) database (http://vistacollaboration.org),12
including age, sex, onset-to-treatment time (OTT),
administration of rt-PA, pre-stroke SSRI exposure,
stroke severity by National Institutes of Health
Stroke Score (NIHSS) at admission (baseline NIHSS)
and in the course of 24 to 48 h (NIHSS_24–48h), mod-
ified Rankin Scale (mRS) at 3 months from stroke
onset, 90 days mortality, time to death, admission
platelet count, baseline glycemia, previous stroke, pre-
admission statin and antiplatelet therapy, hypertension,
diabetes mellitus, history of myocardial infarction
(MCI), atrial fibrillation (aFib), ischemic heart disease
(IHD), congestive heart failure (CHF), and transient
ischemic attacks (TIA). Adverse events (AE) records
were screened for bleeding complications, which were
then categorized into intra- and extracranial bleeding
events. If available, grading information was retrieved
for intracerebral hemorrhages according to the
European Cooperative Acute Stroke Study (ECASS)
radiological classification of post-thrombolysis brain
hemorrhage.13–15 Based on previous reports, we con-
sidered any new occurrence of intracranial hemorrhage
within 36 h from rt-PA administration as symptomatic
intracranial hemorrhage (SICH) and adverse side effect
of rt-PA thrombolysis, if the bleeding was associated
with an NIHSS increase of 4 points or leading to
death within 48 h from thrombolysis treatment.15–21
In addition, we regarded any grade 1 (PH1) and
grade 2 (PH2) parenchymal hematoma (according to
ECASS classification) which newly emerged within
36 h from thrombolysis as a relevant complication of
rt-PA administration, regardless of the availability of
NIHSS data.13–15 Because the available data provided
time points in the format of days from admission, a
limit of 2 days rather than 36 h was chosen for defin-
ing early and rt-PA-related bleeding complications.
Functional outcome at three months was dichotomized
into favorable outcome (mRS 0–2), reflecting
International Journal of Stroke, 0(0)
independence in the daily activities of life, versus
unfavorable outcome (mRS 3–6), indicating death or
dependency. Mortality at seven days was inferred
from time to death data.
Statistical analysis
Patients were categorized into two groups based on
pre-stroke SSRI exposure. To test variables for
confounding effects, pre-stroke SSRI exposure as the
independent treatment variable and one by one the pos-
sible confounders (age, sex, OTT, baseline NIHSS,
admission platelet count and glycemia, previous
stroke, pre-admission statin and antiplatelet therapy,
MCI, aFib, IHD, CHF, TIA) entered a bivariable
binary logistic regression model and the adjusted odds
ratio (OR) was calculated. When the adjusted OR
deviated from the crude OR by >5%, a variable was
recorded as possible confounder. A multivariable
model with the treatment variable and all variables
that shifted the crude OR by >5% was then built.
Moreover, due to their well-documented relation to
outcome in patients with acute ischemic stroke, the
variables age, baseline NIHSS, admission platelet
count, and baseline glycemia entered multivariable ana-
lysis regardless of bivariable testing results.6,16 Two-
sided values of P<.05 were considered as statistically
significant in all tests. Cohen’s ƒ2 effect sizes of .02, .15,
and .35 were regarded as small, medium, and large. All
statistics were performed using statistical software IBM
SPSS Statistics 20.0 for Windows.
Results
Altogether 1114 patient records were included in the
analyses, mean age 72 years (range 36–98; SD 11),
57.6% of patients were male. A total of 135 (36.8%)
patients had previous SSRI treatment. In SSRI naive
patients and pre-stroke SSRI users, OTT (P ¼ .64),
baseline NIHSS (P ¼ .12), and admission glycemia
(P ¼ .48) were comparable. Mean age was lower
(P ¼ .01) in the SSRI group and female sex prevailed
(P<.001). Pre-admission statin (P<.001) and antiplate-
let therapy (P<.001) were less common and admission
platelet count was higher (P ¼ .001) in patients with
pre-stroke SSRI treatment (Table 1).
Intracranial bleeding complications
Out of 1114 thrombolysed patients with ischemic
stroke, 163 (14.6%) patients developed any type of
adverse hemorrhagic event within two days from
thrombolysis. Any type of hemorrhagic transformation
and/or intracranial hemorrhage was reported in 86
Schellen et al. 3

Table 1. Characteristics of SSRI naive patients vs. those treated with SSRI before stroke.

Characteristics
SSRI naive (n ¼ 979) SSRI before stroke (n ¼ 135) P
Age (y), mean (range, SD)a 72 (41–98, 10) 69 (36–92, 13) .001

Sex (female), n (%)b 386 (39.4) 86 (63.7) <.001

OTT (h), median (range, IQR)b 3.5 (1–6, 1) [N ¼ 962] 3.7 (1–6, 1) [N ¼ 134] .64

Baseline NIHSS, median (range, IQR)b 14 (3–30, 9) 13 (5–27, 9) .12

Platelet count (G/l), median (range, IQR)b 215 (90–688, 79) [N ¼ 785] 232 (117–501, 114) [N ¼ 98] .001

Admission glycemia (mmol/l), median 6.7 (2.7–28.0, 2.4) [N ¼ 765] 6.7 (3.6–21.7, 2.5) [N ¼ 114] .48
(range, IQR)b

Pre-stroke statin, n (%)c 506 (51.7) 48 (35.6) <.001

Pre-stroke antiplatelets, n (%)c 801 (81.8) 56 (41.5) <.001

Previous stroke, n (%)c 226 (23.3) [N ¼ 971] 37 (27.8) [N ¼ 133] .28

Hypertension, n (%)c 795 (81.9) [N ¼ 971] 100 (75.8) [N ¼ 132] .10

Diabetes mellitus, n (%)c 252 (26.0) [N ¼ 971] 33 (25.0) [N ¼ 132] .92

History of myocardial infarction, n (%)c 255 (26.3) [N ¼ 971] 27 (20.5) [N ¼ 132] .17

Atrial fibrillation, n (%)c 307 (31.6) [N ¼ 971] 33 (25.0) [N ¼ 132] .13

Ischemic heart disease, n (%)c 368 (47.5) [N ¼ 775] 43 (37.7) [N ¼ 114] .06

Congestive heart failure, n (%)c 109 (13.1) [N ¼ 830] 17 (13.8) [N ¼ 123] .78

Transient ischemic attacks, n (%)c 86 (11.1) [N ¼ 777] 11 (9.6) [N ¼ 115] .75

IQR: interquartile range; N, number of samples, if data were not available from all patients; NIHSS: National Institutes of Health Stroke Score; OTT:
onset-to-treatment time; SSRI: selective serotonin reuptake inhibitors. P-values, aStudent t-test, bMann–Whitney U-test, cFisher’s exact test.

(52.8%) of these patients (7.7% of the study popula-
tion). SICH occurred in 30 (2.7%) out of 1114 throm-
bolysed patients and in 28 (2.9%) SSRI naive versus 2
(1.5%) pre-exposed patients. Early PH1 or PH2 were
observed in a total of 34 (3.1%) patients and in 30
(3.1%) SSRI naive versus 4 (3.0%) pre-exposed
patients (Table 2). Pre-stroke SSRI exposure prior to
rt-PA treatment was neither associated with early ICH
in general (Adj. OR, .60; 95% CI, .17–2.10; P ¼ .42) nor
linked to symptomatic ICH (Adj. OR, .55; 95% CI,
.06–4.71; P ¼ .58) or early PH1 and PH2 bleeding com-
plications (Adj. OR, .31; 95% CI, .04–2.67; P ¼ .29)
(Table 3).
Extracranial bleeding complications
Out of 163 (14.6%) patients with early hemorrhagic
events, 87 (53.4%) patients in total and 76 (7.8%)
SSRI naive versus 11 (8.1%) pre-exposed patients
developed extracranial bleeding complications
(Table 2). Pre-stroke SSRI exposure was not associated
with early extracranial hemorrhages (Adj. OR, .65;
95% CI, .20–2.04; P ¼ .46) (Table 3).
Functional outcome at three months
Functional outcome data were available for 1074
patients (96.4%). Unfavorable outcome occurred in a
total of 663 patients (61.7%) and in 580 (59.2%) SSRI
naive versus 83 (61.5%) pre-exposed patients. An asso-
ciation of pre-stroke SSRI exposure with unfavorable
mRS was not observed. Adjustment for confounders
only had a moderate effect and did not reveal signifi-
cant associations (Adj. OR, 1.33; 95% CI, .72–2.47;
P ¼ .36) (Table 3).
Mortality
Vital status was available for 1114 (100%) patients.
By day 90, 219 patients (19.7%) had died. In patients

International Journal of Stroke, 0(0)

4 International Journal of Stroke 0(0)

Table 2. Bleeding complications, outcome and mortality in SSRI naive patients vs. those treated with SSRI before stroke

Outcome
SSRI naive (n ¼ 979) SSRI before stroke (n ¼ 135) P
Early intracranial hemorrhage, n (%)a 79 (8.1) 7 (5.2) .30

Symptomatic (SICH), n (%)a 28 (2.9) 2 (1.5) .57

HI1 or HI2, n (%)a 4 (.4) 0 (0) >.99

PH1 or PH2, n (%)a 30 (3.1) 4 (3.0) >.99

Early ECH (  2d), n (%)a 76 (7.8) 11 (8.1) .86

NIHSS (24–48 h), median (range, IQR)b 11 (0–38, 12) [N ¼ 778] 10 (0–38, 12) [N ¼ 120] .29

mRS, median (range, IQR)b 3 (0–6, 4) [N ¼ 941] 3 (0–6, 2) [N ¼ 133] .56

Mortality (90 days), n (%)a 203 (20.7) 16 (11.9) .02

Mortality (7 days), n (%)a 93 (9.5) 6 (4.4) .46

Time to death (days), median (range, IQR)b 10 (0–104, 22) [N ¼ 205] 22 (3–92, 35) [N ¼ 17] .07
Early hemorrhage, occurrence at 2 days from thrombolysis; ECASS: European Cooperative Acute Stroke Study; HI: hemorrhagic infarction according
to the ECASS radiological classification of post-thrombolysis brain hemorrhage; HI1: HI grade 1; HI2: HI grade 2; mRS: modified Rankin Scale at three
months; IQR: interquartile range; NIHSS: National Institutes of Health Stroke Score; PH: parenchymal hematoma according to ECASS classification;
PH1: PH grade 1; PH2: PH grade 2; SICH: symptomatic intracranial hemorrhage (early occurrence, NIHSS increase of 4 points or leading to death
within 2 days from thrombolysis). NIHSS (24–48 h), follow-up NIHSS at 24–48 h from admission. P-values, aFischer’s exact test, bMann–Whitney U-test.

Table 3. Binary logistic regression including pre-stroke SSRI exposure to predict bleeding complications, functional outcome at
three months and mortality

Outcome
Crude OR 95% CI P Adj. OR 95% CI P
Early intracranial hemorrhagea,b,c,d .62 .28–1.38 .24 .60 .17–2.10 .42

Symptomatic ICH (SICH)a,b,c,d,e .50 .12–2.13 .35 .55 .06–4.71 .58

PH1 or PH2a,b,c,d,e,f,g .97 .34–2.79 .95 .31 .04–2.67 .29

Early extracranial hemorrhageb,c,d,e,h,i 1.05 .55–2.04 .88 .65 .20–2.04 .46

Unfavorable outcomea,b,c,g,i 1.03 .71–1.50 .86 1.33 .72–2.47 .38

Mortality (7 days)b,c,d,e,h,j .66 .23–1.84 .43 1.15 .27–4.87 .85

Mortality (90 days)b,c,d,e,i .51 .30–.89 .02 .84 .39–1.80 .65

Adj. OR: adjusted odds ratio; CI: confidence interval; early hemorrhage, occurrence at 2 days from thrombolysis; ECASS: European Cooperative
Acute Stroke Study; NIHSS: National Institutes of Health Stroke Score; OR: odds ratio; PH: parenchymal hematoma according to the ECASS
radiological classification of post-thrombolysis brain hemorrhage; PH1: PH grade 1; PH2: PH grade 2; SICH: symptomatic intracranial hemorrhage
(early occurrence, NIHSS increase of 4 points or leading to death within two days from thrombolysis). Adjustment for confounders including age,
baseline NIHSS, admission platelet count, baseline glycemia, and if noted asex, bpre-stroke antiplatelets, cischemic heart disease, dtransient ischemic
attack, econgestive heart failure, fpre-stroke statin, ghypertension, honset-to-treatment time, iatrial fibrillation, jdiabetes mellitus.

with pre-stroke SSRI exposure, mortality was 11.9%
(n ¼ 16) compared to 20.7% (n ¼ 203) in patients
without prior SSRI therapy (Table 1). In univariable
analysis, pre-stroke SSRI exposure was associated
with lower 90-day mortality (crude OR, .51; 95%
CI, .30–.89; P ¼ .02, Cohen’s ƒ2, .01). However,
after adjustment for confounders, the association
was no longer significant. Mortality at seven days
was not associated with pre-stroke SSRI use
(Table 3).

International Journal of Stroke, 0(0)

Schellen et al.
Combined pre-stroke antiplatelet and SSRI
treatment
In view of the significantly lower prevalence of antipla-
telet therapy in patients with pre-stroke SSRI treat-
ment, further exploratory analyses were performed in
those patients with pre-stroke antiplatelet therapy
(n ¼ 857). In compliance with results from the general
study population, pre-stroke SSRI treatment in this
subset of patients showed no association with bleeding
complications (e.g. SICH, Adj. OR 1.24, 95% CI .13–
11.59, P ¼ 0.85), functional outcome (Adj. OR .81,
95% CI .31–2.12, P ¼ .67), or mortality (e.g. 90-day
mortality, Adj. OR .90, 95% CI .09–8.85, P ¼ .93).
Discussion
Our results suggest that pre-stroke SSRI exposure prior
to rt-PA thrombolysis for ischemic stroke does not
increase the risk of intra- or extracranial bleeding com-
plications and is not associated with adverse outcome
or increased mortality.
Positive associations of SSRI treatment with structural
and functional recovery from brain damage following
ischemic stroke have been reported by a growing
number of studies with post-stroke SSRI administration
and linked to a variety of physiological mechanisms.4–11
In contrast to potential beneficial associations in ischemic
stroke patients, SSRI treatment has been linked to bleed-
ing complications and a higher incidence of cerebrovas-
cular events in the general population.1,4,22 Such adverse
effects of SSRI exposure have mainly been attributed to
the inhibition of platelet serotonin reuptake and conse-
quently reduced platelet aggregation and activity.3 In
ischemic stroke patients, SICH is a devastating complica-
tion of thrombolysis treatment and associated with high
morbidity and mortality.15,23 It has previously been
reported that pre-stroke SSRI use is linked to increased
mortality in hemorrhagic stroke patients, but not in
patients with ischemic stroke.5 Other authors have asso-
ciated pre-stroke SSRI use with higher mortality in the
general stroke population,24 unfortunately without
reporting the prevalence of hemorrhagic versus ischemic
stroke. We investigated ischemic stroke patients in more
detail and found that mortality was not associated with
pre-stroke SSRI exposure following rt-PA thrombolysis.
Lower mean age in the SSRI group may explain lower
mortality in univariable comparison.
Reports on functional outcome following rt-PA
thrombolysis in pre-stroke SSRI users are inconclusive.
One study investigating 476 acute ischemic stroke
patients who received thrombolysis treatment reported
a trend towards association with unfavorable outcome
at three months from rt-PA administration,6 however,
non-significant and based on a relatively small sample
5
of pre-stroke SSRI users (n ¼ 22). A significant associ-
ation with unfavorable outcome was only found in
patients with cortical stroke, which we were unable to
separately assess in our study. In a more recent analysis
of 239 ischemic stroke patients, SSRI pretreatment
(n ¼ 51) was linked to favorable outcome at discharge,
in comparison to post-stroke SSRI administration
(n ¼ 188).11 Functional outcome was assessed noticeably
earlier than in previous reports6,10 and in our study, and
hospital stay of patients with pre-stroke SSRI exposure
(median seven days; interquartile range [IQR], five days)
was significantly shorter (P<.001) compared to patients
who were newly treated with SSRI (median 11d; IQR,
6d). The authors did not investigate patients who
received neither pre- nor post-stroke SSRI and excluded
patients who suffered from severe stroke with infaust
prognosis. In comparison, our data showed no relation
between pre-stroke SSRI exposure and functional out-
come at three months. The conflicting results could be
related to different inclusion criteria and outcome meas-
ures (discharge vs. three-month follow-up) or might be
attributed to unknown factors introduced in the later
course of the disease, which were not accounted for in
this study and in previous comparisons. Data on post-
stroke SSRI exposure were not available in our study.
While it is likely that patients with pre-stroke SSRI con-
tinued SSRI treatment after the index stroke, variations
in post-stroke treatment may explain deviating results.
Limitation of our study is the heterogeneous indica-
tion for SSRI treatment and its uncontrolled and non-
randomized administration with insufficient study data
on dosage and/or duration of pre-stroke treatment.
Presumably the majority of SSRI users in this study
received treatment because of depression, which is by
itself associated with increased ischemic stroke risk,7,25
unfavorable functional outcome,26 higher mortality,25
and confounding comorbidity such as cardiac disease.27
Despite having performed a detailed search for possible
confounders in the analysis, confounding by indication
may be a source of bias in this study. Furthermore,
sufficient data were not available to further discriminate
between different types of SSRI and to assess potential
effects of other antidepressants. Finally, the results of
our study have to be interpreted with caution because
of the retrospective, non-randomized nature of the ana-
lysis. Notwithstanding the aforementioned limitations,
the strength of this study is a large prospective patient
cohort with rigorously collected detailed baseline
demographics, precise AE reporting, and standardized
manner and timing of outcome assessments.
Conclusion
Results from this large retrospective comparison indi-
cate that pre-stroke SSRI exposure in ischemic stroke
International Journal of Stroke, 0(0)
6 International Journal of Stroke 0(0)
patients receiving rt-PA is not associated with bleeding
complications, functional outcome or mortality.
However, due to the retrospective and non-randomized
nature of this study, unbiased proof of the SSRI-throm-
bolysis safety cannot be claimed. As far as currently
available data indicate, there is no signal to consider
pre-stroke SSRI exposure to be a risk with regard to rt-
PA thrombolysis.
Acknowledgments
VISTA-Acute Steering Committee members: KR Lees
(Chair), A Alexandrov, PM Bath, E Bluhmki, N Bornstein,
C Chen, L Claesson, SM Davis, G Donnan, HC Diener, M
Fisher, M Ginsberg, B Gregson, J Grotta, W Hacke, MG
Hennerici, M Hommel, M Kaste, P Lyden, J Marler, K
Muir, N Venketasubramanian, R Sacco, A Shuaib, P Teal,
NG Wahlgren, S Warach, and C Weimar.
Authors’ contributions
CS searched the literature, analyzed the data, and wrote the
paper. JF and WL contributed to and reviewed the paper. MS
extracted the data, reviewed, and made critical revisions of
the paper.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
References
1. Hackam DG and Mrkobrada M. Selective serotonin reup-
take inhibitors and brain hemorrhage: a meta-analysis.
Neurology 2012; 79: 1862–1865.
2. McCrea RL, Sammon CJ, Nazareth I and Petersen I.
Initiation and duration of selective serotonin reuptake
inhibitor prescribing over time: UK cohort study. Br J
Psychiatry 2016; 209: 421–426.
3. Gaduputi V, Patel H, Sakam S, Chime C, Balar B and
Kumar K. Serotonin reuptake inhibitors and post-gastro-
stomy bleeding: reevaluating the link. Ther Clin Risk
Manag 2015; 11: 1283.
4. Mortensen JK, Larsson H, Johnsen SP and Andersen G.
Post stroke use of selective serotonin reuptake inhibitors
and clinical outcome among patients with ischemic stroke:
a nationwide propensity score-matched follow-up study.
Stroke 2013; 44: 420–426.
5. Mortensen JK, Larsson H, Johnsen SP and Andersen G.
Impact of prestroke selective serotonin reuptake inhibitor
treatment on stroke severity and mortality. Stroke 2014;
45: 2121–2123.
6. Miedema I, Horvath KM, Uyttenboogaart M, et al. Effect
of selective serotonin re-uptake inhibitors (SSRIs) on
International Journal of Stroke, 0(0)
functional outcome in patients with acute ischemic
stroke treated with tPA. J Neurol Sci 2010; 293: 65–67.
7. Siepmann T, Penzlin AI, Kepplinger J, et al. Selective
serotonin reuptake inhibitors to improve outcome in
acute ischemic stroke: possible mechanisms and clinical
evidence. Brain Behav 2015; 5: e00373.
8. Mead GE, Hsieh C-F, Lee R, et al. Selective serotonin
reuptake inhibitors (SSRIs) for stroke recovery. In: Mead
GE (ed.) Cochrane Database of Systematic Reviews.
Chichester, UK: John Wiley & Sons Ltd, 2012,
p. CD009286.
9. Cramer SC. Drugs to enhance motor recovery after
stroke. Stroke 2015; 46: 2998–3005.
10. Chollet F, Tardy J, Albucher J-F, et al. Fluoxetine for
motor recovery after acute ischaemic stroke (FLAME): a
randomised placebo-controlled trial. Lancet Neurol 2011;
10: 123–130.
11. Siepmann T, Kepplinger J, Zerna C, et al. The effects of
pretreatment versus de novo treatment with selective
serotonin reuptake inhibitors on short-term outcome
after acute ischemic stroke. J Stroke Cerebrovasc Dis
2015; 24: 1886–1892.
12. Ali M, Bath PMW, Curram J, et al. The virtual inter-
national stroke trials archive. Stroke 2007; 38: 1905–1910.
13. Hacke W. Intravenous thrombolysis with recombinant
tissue plasminogen activator for acute hemispheric
stroke. The European Cooperative Acute Stroke Study
(ECASS). JAMA 1995; 274: 1017–1025.
14. Fiorelli M, Bastianello S, von Kummer R, et al.
Hemorrhagic transformation within 36 hours of a cere-
bral infarct : relationships with early clinical deterioration
and 3-month outcome in the European Cooperative
Acute Stroke Study I (ECASS I) cohort. Stroke 1999;
30: 2280–2284.
15. Trouillas P and von Kummer R. Classification and
pathogenesis of cerebral hemorrhages after thrombolysis
in ischemic stroke. Stroke 2006; 37: 556–561.
16. Miller DJ, Simpson JR and Silver B. Safety of thromb-
olysis in acute ischemic stroke: a review of complications,
risk factors, and newer technologies. Neurohospitalist
2011; 1: 138–147.
17. The National Institute of Neurological Disorders and
Stroke rt-PA Stroke Study Group. Tissue plasminogen
activator for acute ischemic stroke. N Engl J Med 1995;
333: 1581–1588.
18. The NINDS t-PA Stroke Study Group. Intracerebral
hemorrhage after intravenous t-PA therapy for ischemic
stroke. Stroke 1997; 28: 2109–2118.
19. del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS,
Rowley HA and Gent M. PROACT: a phase II rando-
mized trial of recombinant pro-urokinase by direct arter-
ial delivery in acute middle cerebral artery stroke. Stroke
1998; 29: 4–11.
20. von Kummer R, Broderick JP, Campbell BCV, et al. The
Heidelberg bleeding classification. Stroke 2015; 46:
2981–2986.
21. Hacke W, Donnan G, Fieschi C, et al. Association of
outcome with early stroke treatment: pooled analysis of
ATLANTIS, ECASS, and NINDS rt-PA stroke trials.
Lancet 2004; 363: 768–774.
Schellen et al.
22. Wu C-S, Wang S-C, Cheng Y-C and Gau SS-F.
Association of cerebrovascular events with antidepres-
sant use: a case-crossover study. Am J Psychiatry 2011;
168: 511–521.
23. Seet RCS and Rabinstein AA. Symptomatic intracranial
hemorrhage following intravenous thrombolysis for acute
ischemic stroke: a critical review of case definitions.
Cerebrovasc Dis 2012; 34: 106–114.
24. Ried LD, Jia H, Feng H, et al. Selective serotonin reup-
take inhibitor treatment and depression are associated
with poststroke mortality. Ann Pharmacother 2011; 45:
888–897.
7
25. Pan A, Sun Q, Okereke OI, Rexrode KM and Hu FB.
Depression and risk of stroke morbidity and mortality.
JAMA 2011; 306: 1241.
26. Aron AW, Staff I, Fortunato G and McCullough LD.
Prestroke living situation and depression contribute to
initial stroke severity and stroke recovery. J Stroke
Cerebrovasc Dis 2015; 24: 492–499.
27. Lichtman JH, Bigger JT, Blumenthal JA, et al.
Depression and coronary heart disease: recommendations
for screening, referral, and treatment. Circulation 2008;
118: 1768–1775.
International Journal of Stroke, 0(0)