Improving Recovery After Stroke

A Role for Antidepressant Medications?

Harold P. Adams, Jr, MD; Robert G. Robinson, MD

lthough stroke is a leading cause of death in the United

States and around the world, many people fear this
disease because of its nonfatal neurological impairments that
lead to disability or dependency. Considerable research has
focused on lessening the neurological effects of the acute
brain injury. To date, success is limited. Despite these
research efforts, only intravenous thrombolysis and endovascular interventions are accepted as effective in limiting the
acute effects of ischemic stroke. Although these therapies are
efficacious, only 3% to 5% of patients with stroke are
receiving reperfusion-based therapies due to the very short
time windows for treatment.1 No medical or surgical intervention is useful in improving outcomes after intracerebral
hemorrhage.
Annually, approximately 400 000 Americans need rehabilitation to help with recovery after stroke.2 Given the magnitude of the problem, effective new therapies are needed to
augment the process of recovery. These therapies could be
given as adjuncts to conventional rehabilitation to these
patients who have potentially disabling residual neurological
impairments. Because many more patients could be treated,
an effective therapy that maximizes neurological recovery
might have a much bigger societal impact than emergency
reperfusion therapy alone.3,4 Unfortunately, relatively few
clinical studies have tested interventions that might augment
recovery. The basic science understandings of the process of
recovery after stroke have advanced.510 It is now clear that
the adult brain has a real capacity for physiological and
anatomic modifications that lead to motor and cognitive
recovery.11 This complex process is mediated by multiple
mechanisms including enhanced regional metabolism and
resolution of diaschisis. Cellular changes after stroke include
proliferation of neural and glial cell precursors, activation of
astrocytes and inflammatory cells, migration of blood vessels,
increased axonal sprouting, increased branching of dendrites,
and development of new synapses.1214 Neurogenesis after
stroke also includes production of progenitor cells in the
subventricular zone, hippocampus, and other brain regions
that migrate into areas of infarction. In experimental models,
the maximal effects are seen within the first 2 to 3 weeks after
stroke and may extend for 3 to 6 months.5

Potential interventions to enhance restorative processes

include administration of growth factors, use of marrow
stromal cells or erythropoietin, robotic assistance, brain
stimulation, and intralesional stem cell transplantation.1518
Some of these interventions likely will be expensive and may
require special expertise, resources, and technology that
could limit their use. Another approach would be the adjunctive use of pharmacological therapies.19 Clinical studies of the
potentially positive impact of medications have begun to
emerge.20,21 Laboratory studies of medications that increase
brain concentrations of brain amines (serotonin, dopamine,
etc), including amphetamines, demonstrate a positive impact
on outcomes.22 However, clinical trials have found conflicting results and some of these medications may not be optimal
for treatment of patients with recent stroke.23
Another promising approach is the use of antidepressants,
particularly in management of patients who are not depressed.
Depression is a common consequence of ischemic stroke; it
occurs in approximately 25% to 30% of patients and it peaks
within the first 3 to 6 months.24 When adjusting for age,
severity of stroke, and other covariables, depression has
major negative effects on cognitive and motor recovery and is
associated with increased mortality and an increased risk of
recurrent vascular events.24,25 However, there have been
concerns about the safety of the antidepressants when given
to elderly patients. In particular, the risk of bleeding may be
increased because of potential interactions with antiplatelet
agents. Some observational studies have reported an increased risk of either hemorrhagic or ischemic stroke among
older patients taking antidepressant medications, whereas
others have not found these associations.26 31 In addition, the
use of antidepressants in preventing depression after stroke
also has been debated. For example, a small randomized trial
reported that early administration of sertraline reduced the
incidence of depression (16.7% [8 of 48] versus 21.6% [11 of
51] for placebo, P0.59).32 However, the nonsignificant
results may be explained in part by the limited number of
patients in the study. Based on a meta-analysis of randomized
trials, Fournier et al33 concluded that the medications were
effective in treating severe depression but of uncertain efficacy in less severely depressed patients. In a rebuttal,
Isaccson and Adler34 noted that the scales used in the trials

Received December 1, 2011; final revision received February 22, 2012; accepted March 22, 2012.
From the Departments of Neurology (H.P.A.) and Psychiatry (R.G.R.), Carver College of Medicine, University of Iowa, Iowa City, IA.
Correspondence to Harold P. Adams, Jr, MD, Department of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242-1053. E-mail
harold-adams@uiowa.edu
(Stroke. 2012;43:2829-2832.)
2012 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org

DOI: 10.1161/STROKEAHA.111.640524

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included in the meta-analysis were not sufficiently sensitive

to detect treatment effects and, thus, the conclusions could
not be sustained. This observation is supported by the
findings of Hackett et al.35 In addition, a Cochrane systemic
review found that antidepressant medications are effective in
treating depression after stroke.36 Another meta-analysis performed by Yi et al37 found that fluoxetine is beneficial for
prevention of poststroke depression although it did not reduce
the severity of the depressive symptoms. Based on the
available data, current American Heart Association guidelines recommend regular screening for depression for stroke
and if depression is detected, antidepressants are advised.38
Given these recommendations, enrolling depressed patients
into a randomized placebo-controlled trial testing the use of
antidepressants in improving neurological outcomes would
be problematic.
Remission of depression is associated with improved
outcomes with rehabilitation, which implies that the administration of antidepressant medications might potentially augment recovery.39 41 Recent data show that antidepressant
medications also might be useful in fostering recovery in
nondepressed patients.41,42 Because antidepressant medications are widely and safely used, they would be strong
candidates to be used as adjunctive agents in the subacute
phase of stroke. The selective serotonin reuptake inhibitors
are of particular interest because of their safety profile in
patients with heart disease and stroke.43,44 Laboratory research also supports the use of selective serotonin reuptake
inhibitors as a tactic to maximize recovery after stroke.45 47
Several clinical studies, testing different agents, have
evaluated the potential use of the selective serotonin reuptake
inhibitor medications in several settings after stroke. When
compared with a control group that received placebo, Dam et
al48 found that fluoxetine (20 mg/day) facilitated motor
recovery among patients receiving physical therapy. Fruehwald et al49 initiated fluoxetine therapy (20 mg/day) within 2
weeks after stroke to 24 patients and continued treatment for
12 weeks; they found sustained benefits from treatment at 18
months when compared with a group of patients treated with
a placebo. In a study using functional MRI, Pariete el al50
reported that a single dose of fluoxetine (20 mg) led to
hyperactivation of the ipsilesional insular and lateral motor51
cortex at 5 hours when compared with placebo; they also
found that fluoxetine improved finger-tapping speed as well
as strength of the paretic arm. In a crossover study of 8
patients with chronic stroke, Zittel et al52 reported that a
single (40 mg) dose of citalopram improved motor performance on a peg board when compared with the responses
among patients receiving placebo. In another study, Acler et
al53 gave citalopram (10 mg/day) for 1 month to 10 patients
with stroke and reported greater improvements in the National Institutes of Health Stroke Scale when compared with
10 patients treated with placebo. Bilge et al39 treated patients
with poststroke depression with citalopram (20 mg/day) for 6
months and found improvements in the scores of the Scandinavian Stroke Scale, modified Rankin Scale, and Barthel
Index at 12 months; the results paralleled improvement in the
depression. Another trial found that paroxetine improved
motor outcomes after stroke.54 A crossover study that in-

cluded functional MRI reported that reboxetine increased grip

strength and finger dexterity and was associated with a
reduction in cortical hyperactivity.51
The 2 largest studies were conducted by Chollet et al44 and
our group.42 In the former study, 57 patients were treated with
fluoxetine (20 mg/day) and 56 patients received placebo for 3
months beginning within 10 days of stroke. All patients
needed rehabilitation and the mean baseline National Institutes of Health Stroke Scale scores were approximately 13 in
both groups. At 3 months, improvements in the Fugl-Meyer
motor scores were significantly higher with fluoxetine (34
points; 95% CI, 29.738.4) than with placebo (24 points; 95%
CI, 19.9 28.7.) Similarly, modified Rankin Scale scores of 0
to 2 were achieved in 26% of fluoxetine-treated patients and
9% of control subjects. In a 3-arm trial that enrolled patients
within 3 months of stroke and treated for 3 months, we
compared 32 patients treated with fluoxetine (40 mg/day), 22
patients treated with nortriptyline (100 mg/day), or 29 patients administered placebo. After controlling for age, depression, rehabilitation intensity, and baseline severity of stroke,
improvements in the modified Rankin Scale were significantly greater at 12 months with treatment (t[156]3.17,
P0.002.)42 Furthermore, follow-up of this group found that
70% of the patients treated with antidepressants had survived
7 years compared with 36% of those given placebo
(P0.001.)42 In another multicenter, randomized, placebocontrolled trial, we demonstrated that escitalopram (10 mg/
day) given for 1 year prevents development of poststroke
depression and was associated with improved short- and
long-term memory recovery, even after controlling for age,
sex, and baseline cognitive function.43,55 These findings are
buttressed by the results of the project of Simis and Nitrin56
who reported that citalopram was associated with improved
memory and attention.
Although these studies are relatively small, they demonstrate
the potentially positive impact of the adjunctive use of selective
serotonin reuptake inhibitor medications in treatment of nondepressed patients with recent stroke.3 Interest in the potential
efficacy of antidepressants in improving outcomes after stroke,
especially in nondepressed patients, is considerable. The selective serotonin reuptake inhibitors appear to augment motor and
cognitive recovery. The medications seem to be relatively safe in
patients with stroke.43,44,55 Because the prices of the medications are relatively inexpensive (for example, US $4 per
month for fluoxetine), the cost-effectiveness of these agents
could be considerable. Although the preliminary data are
promising, they are not definitive. A recommendation for
widespread use of antidepressants in the management of
patients with recent stroke is premature. Larger trials are
needed to test the use of antidepressants in a broad range of
patients with recent stroke. If these trials replicate the results
of the recent studies, the overall impact of adjunctive antidepressant therapy could represent a major advance in the care
of persons surviving stroke.

Disclosures
Dr Adams is a consultant (member of adjudication panel) for Merck
$10 000; a consultant (member of safety panel) for Medtronic
$10 000; and has received grant support from the National Insti-

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Adams and Robinson

tutes of Neurological Disorders and Stroke $10 000. Dr Robinson
is a consultant for Avanir $10 000 and an expert witness
$10 000.

27.

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KEY WORDS: antidepressant medications
hibitors stroke recovery

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selective serotonin reuptake in-

Improving Recovery After Stroke: A Role for Antidepressant Medications?

Harold P. Adams, Jr and Robert G. Robinson
Stroke. 2012;43:2829-2832; originally published online August 2, 2012;
doi: 10.1161/STROKEAHA.111.640524
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2012 American Heart Association, Inc. All rights reserved.
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