Improving Recovery After StrokeA Role for Antidepressant
Medications?
Harold P. Adams, Jr, MD; Robert G. Robinson, MD
Although stroke is a leading cause of death in the UnitedStates
and around the world, many people fear thisdisease because of its
nonfatal neurological impairments thatlead to disability or
dependency. Considerable research hasfocused on lessening the
neurological effects of the acutebrain injury. To date, success is
limited. Despite theseresearch efforts, only intravenous
thrombolysis and endovas-cular interventions are accepted as
effective in limiting theacute effects of ischemic stroke. Although
these therapies areefficacious, only 3% to 5% of patients with
stroke arereceiving reperfusion-based therapies due to the very
shorttime windows for treatment.1 No medical or surgical
inter-vention is useful in improving outcomes after
intracerebralhemorrhage.
Annually, approximately 400 000 Americans need rehabil-itation
to help with recovery after stroke.2 Given the magni-tude of the
problem, effective new therapies are needed toaugment the process
of recovery. These therapies could begiven as adjuncts to
conventional rehabilitation to thesepatients who have potentially
disabling residual neurologicalimpairments. Because many more
patients could be treated,an effective therapy that maximizes
neurological recoverymight have a much bigger societal impact than
emergencyreperfusion therapy alone.3,4 Unfortunately, relatively
fewclinical studies have tested interventions that might
augmentrecovery. The basic science understandings of the process
ofrecovery after stroke have advanced.510 It is now clear thatthe
adult brain has a real capacity for physiological andanatomic
modifications that lead to motor and cognitiverecovery.11 This
complex process is mediated by multiplemechanisms including
enhanced regional metabolism andresolution of diaschisis. Cellular
changes after stroke includeproliferation of neural and glial cell
precursors, activation ofastrocytes and inflammatory cells,
migration of blood vessels,increased axonal sprouting, increased
branching of dendrites,and development of new synapses.1214
Neurogenesis afterstroke also includes production of progenitor
cells in thesubventricular zone, hippocampus, and other brain
regionsthat migrate into areas of infarction. In experimental
models,the maximal effects are seen within the first 2 to 3 weeks
afterstroke and may extend for 3 to 6 months.5
Potential interventions to enhance restorative processesinclude
administration of growth factors, use of marrowstromal cells or
erythropoietin, robotic assistance, brainstimulation, and
intralesional stem cell transplantation.1518Some of these
interventions likely will be expensive and mayrequire special
expertise, resources, and technology thatcould limit their use.
Another approach would be the adjunc-tive use of pharmacological
therapies.19 Clinical studies of thepotentially positive impact of
medications have begun toemerge.20,21 Laboratory studies of
medications that increasebrain concentrations of brain amines
(serotonin, dopamine,etc), including amphetamines, demonstrate a
positive impacton outcomes.22 However, clinical trials have found
conflict-ing results and some of these medications may not be
optimalfor 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;
itoccurs in approximately 25% to 30% of patients and it peakswithin
the first 3 to 6 months.24 When adjusting for age,severity of
stroke, and other covariables, depression hasmajor negative effects
on cognitive and motor recovery and isassociated with increased
mortality and an increased risk ofrecurrent vascular events.24,25
However, there have beenconcerns about the safety of the
antidepressants when givento elderly patients. In particular, the
risk of bleeding may beincreased because of potential interactions
with antiplateletagents. Some observational studies have reported
an in-creased risk of either hemorrhagic or ischemic stroke
amongolder patients taking antidepressant medications,
whereasothers have not found these associations.2631 In addition,
theuse of antidepressants in preventing depression after strokealso
has been debated. For example, a small randomized trialreported
that early administration of sertraline reduced theincidence of
depression (16.7% [8 of 48] versus 21.6% [11 of51] for placebo,
P0.59).32 However, the nonsignificantresults may be explained in
part by the limited number ofpatients in the study. Based on a
meta-analysis of randomizedtrials, Fournier et al33 concluded that
the medications wereeffective in treating severe depression but of
uncertain effi-cacy 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
[email protected](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 sensitiveto
detect treatment effects and, thus, the conclusions couldnot be
sustained. This observation is supported by thefindings of Hackett
et al.35 In addition, a Cochrane systemicreview found that
antidepressant medications are effective intreating depression
after stroke.36 Another meta-analysis per-formed by Yi et al37
found that fluoxetine is beneficial forprevention of poststroke
depression although it did not reducethe severity of the depressive
symptoms. Based on theavailable data, current American Heart
Association guide-lines recommend regular screening for depression
for strokeand if depression is detected, antidepressants are
advised.38Given these recommendations, enrolling depressed
patientsinto a randomized placebo-controlled trial testing the use
ofantidepressants in improving neurological outcomes wouldbe
problematic.
Remission of depression is associated with improvedoutcomes with
rehabilitation, which implies that the admin-istration of
antidepressant medications might potentially aug-ment recovery.3941
Recent data show that antidepressantmedications also might be
useful in fostering recovery innondepressed patients.41,42 Because
antidepressant medica-tions are widely and safely used, they would
be strongcandidates to be used as adjunctive agents in the
subacutephase of stroke. The selective serotonin reuptake
inhibitorsare of particular interest because of their safety
profile inpatients with heart disease and stroke.43,44 Laboratory
re-search also supports the use of selective serotonin
reuptakeinhibitors as a tactic to maximize recovery after
stroke.4547
Several clinical studies, testing different agents,
haveevaluated the potential use of the selective serotonin
reuptakeinhibitor medications in several settings after stroke.
Whencompared with a control group that received placebo, Dam etal48
found that fluoxetine (20 mg/day) facilitated motorrecovery among
patients receiving physical therapy. Frueh-wald et al49 initiated
fluoxetine therapy (20 mg/day) within 2weeks after stroke to 24
patients and continued treatment for12 weeks; they found sustained
benefits from treatment at 18months when compared with a group of
patients treated witha placebo. In a study using functional MRI,
Pariete el al50reported that a single dose of fluoxetine (20 mg)
led tohyperactivation of the ipsilesional insular and lateral
motor51cortex at 5 hours when compared with placebo; they alsofound
that fluoxetine improved finger-tapping speed as wellas strength of
the paretic arm. In a crossover study of 8patients with chronic
stroke, Zittel et al52 reported that asingle (40 mg) dose of
citalopram improved motor perfor-mance on a peg board when compared
with the responsesamong patients receiving placebo. In another
study, Acler etal53 gave citalopram (10 mg/day) for 1 month to 10
patientswith stroke and reported greater improvements in the
Na-tional Institutes of Health Stroke Scale when compared with10
patients treated with placebo. Bilge et al39 treated patientswith
poststroke depression with citalopram (20 mg/day) for 6months and
found improvements in the scores of the Scan-dinavian Stroke Scale,
modified Rankin Scale, and BarthelIndex at 12 months; the results
paralleled improvement in thedepression. Another trial found that
paroxetine improvedmotor outcomes after stroke.54 A crossover study
that in-
cluded functional MRI reported that reboxetine increased
gripstrength and finger dexterity and was associated with
areduction in cortical hyperactivity.51
The 2 largest studies were conducted by Chollet et al44 andour
group.42 In the former study, 57 patients were treated
withfluoxetine (20 mg/day) and 56 patients received placebo for
3months beginning within 10 days of stroke. All patientsneeded
rehabilitation and the mean baseline National Insti-tutes of Health
Stroke Scale scores were approximately 13 inboth groups. At 3
months, improvements in the Fugl-Meyermotor scores were
significantly higher with fluoxetine (34points; 95% CI, 29.738.4)
than with placebo (24 points; 95%CI, 19.928.7.) Similarly, modified
Rankin Scale scores of 0to 2 were achieved in 26% of
fluoxetine-treated patients and9% of control subjects. In a 3-arm
trial that enrolled patientswithin 3 months of stroke and treated
for 3 months, wecompared 32 patients treated with fluoxetine (40
mg/day), 22patients treated with nortriptyline (100 mg/day), or 29
pa-tients administered placebo. After controlling for age,
depres-sion, rehabilitation intensity, and baseline severity of
stroke,improvements in the modified Rankin Scale were
signifi-cantly greater at 12 months with treatment
(t[156]3.17,P0.002.)42 Furthermore, follow-up of this group found
that70% of the patients treated with antidepressants had survived7
years compared with 36% of those given placebo(P0.001.)42 In
another multicenter, randomized, placebo-controlled trial, we
demonstrated that escitalopram (10 mg/day) given for 1 year
prevents development of poststrokedepression and was associated
with improved short- andlong-term memory recovery, even after
controlling for age,sex, and baseline cognitive function.43,55
These findings arebuttressed by the results of the project of Simis
and Nitrin56who reported that citalopram was associated with
improvedmemory and attention.
Although these studies are relatively small, they demonstratethe
potentially positive impact of the adjunctive use of
selectiveserotonin reuptake inhibitor medications in treatment of
nonde-pressed patients with recent stroke.3 Interest in the
potentialefficacy of antidepressants in improving outcomes after
stroke,especially in nondepressed patients, is considerable. The
selec-tive serotonin reuptake inhibitors appear to augment motor
andcognitive recovery. The medications seem to be relatively safe
inpatients with stroke.43,44,55 Because the prices of the
medica-tions are relatively inexpensive (for example, US $4
permonth for fluoxetine), the cost-effectiveness of these
agentscould be considerable. Although the preliminary data
arepromising, they are not definitive. A recommendation
forwidespread use of antidepressants in the management ofpatients
with recent stroke is premature. Larger trials areneeded to test
the use of antidepressants in a broad range ofpatients with recent
stroke. If these trials replicate the resultsof the recent studies,
the overall impact of adjunctive antide-pressant therapy could
represent a major advance in the careof persons surviving
stroke.
DisclosuresDr 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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tutes of Neurological Disorders and Stroke $10 000. Dr
Robinsonis a consultant for Avanir $10 000 and an expert witness$10
000.
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