Selective Serotonin Reuptake Inhibitors for Stroke Recovery
2013; Lippincott Williams & Wilkins; Volume: 44; Issue: 3 Linguagem: Inglês
10.1161/strokeaha.112.673947
ISSN1524-4628
AutoresGillian Mead, Cheng‐Fang Hsieh, Rebecca Lee, М А Кутлубаев, Anne Claxton, Graeme J. Hankey, Maree L. Hackett,
Tópico(s)Pain Management and Treatment
ResumoHomeStrokeVol. 44, No. 3Selective Serotonin Reuptake Inhibitors for Stroke Recovery Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBSelective Serotonin Reuptake Inhibitors for Stroke RecoveryA Systematic Review and Meta-analysis Gillian E. Mead, MD, FRCP, Cheng-Fang Hsieh, MD, Rebecca Lee, MRCP, Mansur Kutlubaev, MD, Anne Claxton, BSc, Graeme J. Hankey, MD, FRACP and Maree Hackett, PhD Gillian E. MeadGillian E. Mead From the Geriatric Medicine, Royal Infirmary, Little France Crescent, Edinburgh, United Kingdom (G.E.M); Division of Geriatrics and Gerontology, Department of Internal Medicine, and Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan (C.-F.H.); NHS Fife, Scotland (R.L.); Department of Neurology, Kuvatov's Republican Clinical Hospital, Ufa, Russia (M.K.); Department of Neurology, Royal Perth Hospital, Perth, Australia (A.C.); Stroke Unit, Department of Neurology, Royal Perth Hospital, Perth, Australia (G.J.H.); and George Institute for Global Health, Sydney, Australia (M.H.). , Cheng-Fang HsiehCheng-Fang Hsieh From the Geriatric Medicine, Royal Infirmary, Little France Crescent, Edinburgh, United Kingdom (G.E.M); Division of Geriatrics and Gerontology, Department of Internal Medicine, and Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan (C.-F.H.); NHS Fife, Scotland (R.L.); Department of Neurology, Kuvatov's Republican Clinical Hospital, Ufa, Russia (M.K.); Department of Neurology, Royal Perth Hospital, Perth, Australia (A.C.); Stroke Unit, Department of Neurology, Royal Perth Hospital, Perth, Australia (G.J.H.); and George Institute for Global Health, Sydney, Australia (M.H.). , Rebecca LeeRebecca Lee From the Geriatric Medicine, Royal Infirmary, Little France Crescent, Edinburgh, United Kingdom (G.E.M); Division of Geriatrics and Gerontology, Department of Internal Medicine, and Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan (C.-F.H.); NHS Fife, Scotland (R.L.); Department of Neurology, Kuvatov's Republican Clinical Hospital, Ufa, Russia (M.K.); Department of Neurology, Royal Perth Hospital, Perth, Australia (A.C.); Stroke Unit, Department of Neurology, Royal Perth Hospital, Perth, Australia (G.J.H.); and George Institute for Global Health, Sydney, Australia (M.H.). , Mansur KutlubaevMansur Kutlubaev From the Geriatric Medicine, Royal Infirmary, Little France Crescent, Edinburgh, United Kingdom (G.E.M); Division of Geriatrics and Gerontology, Department of Internal Medicine, and Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan (C.-F.H.); NHS Fife, Scotland (R.L.); Department of Neurology, Kuvatov's Republican Clinical Hospital, Ufa, Russia (M.K.); Department of Neurology, Royal Perth Hospital, Perth, Australia (A.C.); Stroke Unit, Department of Neurology, Royal Perth Hospital, Perth, Australia (G.J.H.); and George Institute for Global Health, Sydney, Australia (M.H.). , Anne ClaxtonAnne Claxton From the Geriatric Medicine, Royal Infirmary, Little France Crescent, Edinburgh, United Kingdom (G.E.M); Division of Geriatrics and Gerontology, Department of Internal Medicine, and Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan (C.-F.H.); NHS Fife, Scotland (R.L.); Department of Neurology, Kuvatov's Republican Clinical Hospital, Ufa, Russia (M.K.); Department of Neurology, Royal Perth Hospital, Perth, Australia (A.C.); Stroke Unit, Department of Neurology, Royal Perth Hospital, Perth, Australia (G.J.H.); and George Institute for Global Health, Sydney, Australia (M.H.). , Graeme J. HankeyGraeme J. Hankey From the Geriatric Medicine, Royal Infirmary, Little France Crescent, Edinburgh, United Kingdom (G.E.M); Division of Geriatrics and Gerontology, Department of Internal Medicine, and Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan (C.-F.H.); NHS Fife, Scotland (R.L.); Department of Neurology, Kuvatov's Republican Clinical Hospital, Ufa, Russia (M.K.); Department of Neurology, Royal Perth Hospital, Perth, Australia (A.C.); Stroke Unit, Department of Neurology, Royal Perth Hospital, Perth, Australia (G.J.H.); and George Institute for Global Health, Sydney, Australia (M.H.). and Maree HackettMaree Hackett From the Geriatric Medicine, Royal Infirmary, Little France Crescent, Edinburgh, United Kingdom (G.E.M); Division of Geriatrics and Gerontology, Department of Internal Medicine, and Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan (C.-F.H.); NHS Fife, Scotland (R.L.); Department of Neurology, Kuvatov's Republican Clinical Hospital, Ufa, Russia (M.K.); Department of Neurology, Royal Perth Hospital, Perth, Australia (A.C.); Stroke Unit, Department of Neurology, Royal Perth Hospital, Perth, Australia (G.J.H.); and George Institute for Global Health, Sydney, Australia (M.H.). Originally published29 Jan 2013https://doi.org/10.1161/STROKEAHA.112.673947Stroke. 2013;44:844–850Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2013: Previous Version 1 IntroductionEach year, about 16 million people in the world experience a first-ever stroke. Of these, about 5.7 million die and another 5 million remain disabled.1 Although there are effective treatments that restore brain perfusion and minimize complications and recurrent stroke, there is no treatment proven to facilitate neurological recovery after stroke.A recent small trial demonstrated that the selective serotonin reuptake inhibitor (SSRI) fluoxetine, commonly used to treat depression, improved motor recovery and reduced dependency after stroke when given to people without depression.2 Experimental studies reporting neurogenic and neuroprotective effects of SSRIs3,4 provide a plausible mechanism of action.Our objective was to systematically review and perform a meta-analysis of all (published and unpublished) randomized controlled trials of SSRI compared with control, given within the first year of stroke, to determine the effect on dependency, disability, and other important clinical outcomes.MethodsSearches and Study SelectionExtensive literature searches were performed between August 2011 and March 2012 (see Data in online-only Data Supplement); this included searching the gray literature. Two review authors scrutinized the searches of Cochrane Stroke Group, CENTRAL, CCDAN and the trials registers, and applied inclusion criteria. One review author scrutinized the other searches and applied inclusion criteria.We included all randomized controlled trials in patients with a clinical diagnosis of stroke, in which SSRIs were given within the first year of stroke, for any clinical indication. The control arm included usual care or a placebo.Any drug classified as an SSRI (for example fluvoxamine, fluoxetine, sertraline, citalopram, escitalopram, and paroxetine) given at any dose, by any mode of delivery, was included. Drugs with mixed effects were not included.Two review authors independently extracted data, except for papers in Chinese, for which 1 review author extracted data.OutcomesThe primary outcomes were dependence and disability. The secondary outcomes were neurological impairments, depression, anxiety, quality of life, fatigue, healthcare cost, death, leaving the trial early, death, and adverse events including gastrointestinal side effects, bleeding, and seizures.Risk of BiasThe Cochrane Collaboration's risk of bias tool assessed risk of bias in relation to randomization, allocation concealment, blinding, incomplete outcome data, and selective reporting.5 A Funnel plot assessed publication bias.Synthesis of ResultsFor trials with a control arm and 2 active arms, data from the control arm and the SSRI arm were included. Review Manager (RevMan 5.1) software6 calculated summary statistics at the end of intervention and at the end of follow-up. Statistical heterogeneity between trials and subgroups was assessed by I2 statistic and interpreted according to The Cochrane Handbook.5Summary MeasuresRandom effects meta-analyses were performed, using risk ratios (RRs) for dichotomous data and for ordinal scales with a recognized cut point. Standardized mean difference (SMD) was used for ordinal scales and continuous data.Additional AnalysesSubgroup analyses were performed according to type of SSRI, depression or not as an inclusion criterion and time since stroke at recruitment. Sensitivity analyses explored the influence of randomization, allocation concealment, blinding, incomplete outcome data, and selective reporting on effect sizes.ResultsStudy SelectionAfter removal of duplicates, there were 4164 records. Two hundred twenty-four full texts were retrieved for scrutinization (Figure 1).Download figureDownload PowerPointFigure 1. Flow diagram for selection of studies.Study CharacteristicsFour trials fulfilled inclusion criteria but provided no data for meta-analysis. A further 51 completed trials provided data for meta-analysis, 1 of which reported data separately for depressed and nondepressed people,7 therefore we considered this as 2 separate trials.Thus, there were 52 trials randomizing 4059 patients to SSRI or control; 28 used fluoxetine,2,7–32 7 used sertraline,33–39 10 used paroxetine,40–49 5 used citalopram,50–54 1 used escitalopram,55 and 1 used either sertraline or fluoxetine.56 The usual care arm was not the same in all the trials because of geographical variation in the management of stroke. In some of the Chinese trials, usual care included agents such as free radical scavengers, hyperbaric oxygen, acupuncture, Ginkgo biloba, deproteinized calf blood, and Vitamin E. These drugs were generally not given as routine care in the trials from the West.Subject CharacteristicsOf the 52 trials included in the meta-analysis, the mean age of patients ranged from 55 years24 to 77 years.35 Most excluded those with dementia or communication difficulties. The mean time since stroke was 0 to 3 months in 36 trials,2,7,9,10,12–16,18,20–25,27–29,31–33,35,38,39,41,43,44,46,48–52,55 3 to 6 months in 4 trials,11,37,47,54 6 to 9 months in 2 trials,36,53 and not reported in 10 trials.8,17,19,26,30,34,42,45,56In 16 trials, a diagnosis of depression (however made) was not one of the inclusion criteria.2,7,8,11,14,18,20,24,27,31,32,34,38,46,50,55 In the other 36 trials, participants had to have depression to be included. Five ongoing trials were identified (see Data in the online-only Data Supplement).Risk of Bias Within TrialsIn a substantial number of trials, there was high or unclear risk of bias for each risk of bias item (Figure 2).Download figureDownload PowerPointFigure 2. Review authors' assessment of risk of bias presented as percentages across all included studies.Results: At End of TreatmentDependencyOne trial recruited 118 patients and reported modified Rankin score at 90 days after randomization in 112 patients. Random allocation to SSRI was associated with reduction in dependency (modified Rankin score >3) (74% SSRI versus 91% placebo; RR, 0.81; 95% confidence interval [CI], 0.68 to 0.97).2DisabilityFigure 3 shows that among 22 randomized controlled trials that measured disability at the end of treatment in a total of 1343 participants, the SMD in disability score was 0.91 (95% CI, 0.60 to 1.22) among participants assigned SSRI compared with placebo. However, there was substantial heterogeneity among the trials (I2=86%; P<0.00001) and moderate heterogeneity between the SSRIs (I2=58%; P=0.7).5 There was also substantial heterogeneity according to time between stroke onset and randomization (I2=89%; P<0.00001), with the largest effect size when time since stroke was not reported.Download figureDownload PowerPointFigure 3. Forest plot of disability at the end of treatment. CI indicates confidence interval; and SSRI, selective serotonin reuptake inhibitor.Figure 4 shows that the magnitude of the effect of SSRI versus placebo on disability was greater in trials that recruited people with depression (SMD, 1.11; 95% CI, 0.71 to 1.51) compared with people who did not have depression at randomization (SMD, 0.49; 95% CI, 0.17 to 0.80; I2=83%, P=0.02). Several disability scales were used including the Barthel, modified Barthel, and functional independence measure. Some Chinese papers used an activities of daily living score that was not referenced.Download figureDownload PowerPointFigure 4. Forest plot of disability at the end of treatment, according to whether depression was present at recruitment. CI indicates confidence interval; and SSRI, selective serotonin reuptake inhibitor.Neurological Deficit ScoreThe SMD was −1.00 (95% CI, −1.26 to −0.75; 29 trials, 2011 participants), with high heterogeneity among trials (I2=86%; P<0.00001), moderate heterogeneity (I2=61%; P=0.04) between type of SSRI and low heterogeneity according to time since stroke (I2=26%; P=0.26). Effect sizes were larger if depression was present at recruitment (I2=76.9%; P=0.04).CognitionSMD was 0.32 (95% CI, −0.23 to 0.86; 7 trials, n=425) with high heterogeneity among trials (I2=86%; P<0.00001) and between type of SSRI (I2;=92.6%; P<0.00001), no heterogeneity according to time since stroke (I2=0%; P=0.64), and moderate heterogeneity according to depression at recruitment (I2=49.8%; P=0.16).Motor DeficitsSMD was −0.33 (95% CI, −1.22 to 0.56; 2 trials, n=145), with heterogeneity in relation to time since stroke (I2=80%; P=0.02).Continuous DepressionSMD was −1.91 (95% CI, −2.34 to −1.48; 39 trials, 2728 participants) with high heterogeneity among trials (I2=95%; P<0.00001) and between type of SSRI (I2=78%; P=0.001), with the largest effect for paroxetine and the smallest for sertraline. There was no heterogeneity according to time since stroke (I2=0%; P=0.66), and moderate heterogeneity between subgroups according to presence of depression at recruitment, (I2=35.5%; P=0.21).Dichotomous Depression ScoresRR was 0.43 (95% CI, 0.24 to 0.77; 8 trials n=771), with high heterogeneity among trials (I2=77%; P<0.0001) and no heterogeneity between SSRIs (I2=0%). There was high heterogeneity according to time since stroke (I2=93%; P=0.00001), with the larger effect size seen in the trials that recruited patients within the first 3 months of stroke. Effect sizes were larger if depression was present at recruitment (I2=86.5%; P=0.007).AnxietySMD was −0.77 (95% CI, −1.52 to −0.02; 8 trials, n=413) with high heterogeneity among trials (I2=92%; P<0.00001) and among type of SSRI (I2=70.6%; P=0.03), with the largest effect seen for paroxetine. Depression at recruitment did not influence effect sizes (I2=29.7%; P=0.23).DeathRR was 0.76 (95% CI, 0.34 to 1.70; 46 trials, n=3344). There was no heterogeneity among trials (I2=0%; P=0.85), type of SSRI (I2=0%; P=0.69) or according to time since stroke (I2=0%; P=0.56) and depression at onset (I2=0%; P=0.66).SeizuresRR was 2.67 (95% CI, 0.61 to 11.63; 7 trials, n=444) in favor of control, with no heterogeneity among trials (I2=0%) or between subgroups.Gastrointestinal Side EffectsRR was 1.90 (95% CI, 0.94 to 3.85; 14 trials, n=902), with low heterogeneity among trials (I2=31%; P=0.14), moderate heterogeneity among type of SSRI (I2=48.9%; P=0.14), and no heterogeneity among the other subgroups.BleedingRR was 1.63 (95% CI, 0.2 to 13.05; 2 trials, n=347), with no heterogeneity.Premature Trial Withdrawal (Before the End of Treatment)RR was 1.02 (95% CI, 0.86 to 1.21; 49 trials, n=3851) in favor of control, with no heterogeneity among trials or subgroups.Follow-up Beyond Treatment EndOnly 8 trials7,10,13,26,33,34,36 followed-up participants beyond the treatment period; 1 did not provide any long-term data.34For disability (2 trials, n=155), and neurological impairment (4 trials, n=275), there were nonsignificant benefits of SSRI (SMD, 1.78; 95% CI, −1.01 to 4.57 and SMD, −0.63; 95% CI, −1.30 to 0.04), respectively. SSRI improved continuous depression scores, (SMD, −1.10; 95% CI, −2.16 to −0.04; 4 trials, n=275) but not dichotomous depression scores (RR, 0.77 [95% CI, 0.34 to 1.76]; 1 trial, n=99). There were no statistically significant differences between SSRI and control for dependence and cognition.Sensitivity AnalysesSensitivity analyses for dependence could not be performed because there was only 1 trial.2 For trials at low risk of bias for each of randomization, allocation concealment, patient/personnel blinding, outcome assessor blinding, incomplete data reporting, and selective reporting, effect sizes were smaller for disability and for all the secondary outcomes, whereas the risk of seizures and gastrointestinal side effects remained similar. Data are available on request. The funnel plot for one of the primary outcomes (disability at the end of treatment) appeared to be asymmetrical on visual inspection (Figure 5).5Download figureDownload PowerPointFigure 5. Funnel plot for disability at the end of treatment. Note that it appears to be asymmetric on visual inspection. SMD indicates standardized mean difference.DiscussionThis is the most comprehensive and up-to-date systematic review of SSRIs in stroke. It includes 52 completed trials in which 4059 patients were recruited. We had not expected to identify such a large number of trials, based on our knowledge of previous reviews. Much of the literature is from China. At the end of treatment, patients allocated an SSRI were less likely to be dependent, disabled, neurologically impaired, depressed, or anxious. The favorable effects of SSRIs on disability, dichotomous depression scores, and neurological deficit scores were greater in participants who were depressed at randomization, but this may have been confounded by study quality—we noted that trials recruiting people with depression tended to have a higher risk of bias than the trials recruiting patients without depression at onset (data available on request). Participants who were allocated an SSRI manifested a trend toward a higher risk of gastrointestinal side effects, seizures, and bleeding. We noted that there was some heterogeneity between type of SSRI (eg, paroxetine appeared to have larger effects sizes on neurological deficit, but this may have been confounded by a higher risk of bias in the paroxetine trials).The SMD of 0.91 (95% CI, 0.60 to 1.22) for disability represents a favorable and potentially important clinical effect of SSRIs. However, the precision and external validity of the estimates are potentially compromised by the substantial clinical and methodological heterogeneity among the many trials. Further, the magnitude of the effect of SSRIs was smaller when only trials at low risk of bias were included.The strengths of our study are that we performed extensive searches, included a wide range of important clinical outcomes, and performed prespecified subgroup and sensitivity analyses. We were unable to identify a second review author who was fluent in Chinese to perform double data extraction, but the majority of Chinese papers had English abstracts, which were checked by a second review author, so it unlikely that there were any important errors in data extraction.The potential weaknesses of our study are that trials had methodological limitations: most were small, there was patchy reporting of outcomes other than depression, none of the trials reported fatigue or health care costs, only 8 trials followed-up patients after completion of treatment, and there were multiple sources of bias, leading to overestimation of effect sizes. There was substantial heterogeneity among trials; there are several possible reasons for this, including differences in the clinical characteristics of patients (eg, age, socioeconomic status, unmeasured difference in baseline variables, time since stroke, depression or not at recruitment, type of SSRI), process of stroke care, duration of treatment with SSRI or placebo, and methodological quality of the trials. The heterogeneity among the trials means that the results become less reliable. We considered whether there was too much heterogeneity for some of the outcomes (eg, disability, neurological impairment, depression, anxiety) to combine results in a meta-analysis and produce a pooled estimate. However, we noted that there was no heterogeneity in the analyses of seizures, gastrointestinal side effects, which suggests that the patient population and treatments were sufficiently similar (at least in the trials that reported these outcomes) to combine data. The use of SMD in meta-analysis assumes that the differences in standard deviations among studies reflect differences in measurement scales and not real differences in variability among study populations. We decided that the trials were sufficiently similar in terms of population (stroke) and drugs (SSRI) to use SMD.The alternative to performing a meta-analysis would have been to perform a narrative review of the 52 studies, but this would have been less easy for the reader to interpret. Furthermore, it would have also been susceptible to subjective interpretation of the data by the review authors.The results of the meta-analysis are in broad agreement with older systematic reviews57–64 that all had much narrower research questions. Our sensitivity analyses suggest that other reviews may have overestimated effect sizes because of the inclusion of less methodologically robust trials.57–62 Two previous Cochrane reviews of interventions (including SSRIs) to treat and prevent depression after stroke63,64 excluded studies that provided usual care without a placebo as the comparator and reported smaller effects than in the current review.The included trials mostly recruited patients aged between 60 and 70 years who were able to consent for themselves. This is an important limitation of the existing data, because the risks and benefits of SSRIs may be different for patients with aphasia or cognitive impairment. Data for hemorrhagic and ischemic stroke were not reported separately. Current practice is often to give an antidepressant (often an SSRI) to stroke survivors with depression; the results of this review tentatively support the use of SSRIs in stroke survivors with depression.This review provided tantalizing evidence of benefits of SSRIs in patients without depression (Figure 4). If the effects are real, and if the risk of adverse events is sufficiently low, SSRIs would become an important (and low cost) treatment for stroke patients. Several ongoing trials were identified (see Data in the online-only Data Supplement) that should together provide the necessary evidence to support or refute the routine prescription of SSRI for patients early after stroke, including those with cognitive impairment and aphasia.AcknowledgmentsBrenda Thomas, Hazel Fraser (Cochrane Stroke Group) and Maureen Harding supported production of the review. This is an abridged version of a Cochrane review published in the Cochrane Library. Wiley has given permission for co-publication.Sources of FundingThe Scottish Stroke Research network and the UK Stroke Research Network helped fund the searches, consumables, and interlibrary loans. During the completion of this work, Dr Hackett was in receipt of a National Health and Medical Research Council Population Health Career Development Award632925 (2010–2013).DisclosuresAll authors have completed the Unified competing interest form at http://www.icmje.org/co_disclosure.pdf. Dr Mead is a coprincipal investigator of FOCUS trial. Drs Hankey and Hackett are coprincipal investigators of AFFINITY Trial. Dr Hankey has received consultancy fees from Bayer Health Care, Boehringer Ingelheim, and Johnson and Johnson. The other authors have no conflicts to report.FootnotesThe online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.112.673947/-/DC1.Correspondence to Gillian E. 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