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. 2021 Nov 15;11(11):CD009286.
doi: 10.1002/14651858.CD009286.pub4.

Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery

Lynn A Legg  1 , Ann-Sofie Rudberg  2 , Xing Hua  3 , Simiao Wu  3 , Maree L Hackett  4 , Russel Tilney  5 , Linnea Lindgren  6 , Mansur A Kutlubaev  7 , Cheng-Fang Hsieh  8 , Amanda J Barugh  9 , Graeme J Hankey  10 , Erik Lundström  6 , Martin Dennis  11 , Gillian E Mead  11
Affiliations

Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery

Lynn A Legg et al. Cochrane Database Syst Rev. .

Abstract

Background: Selective serotonin reuptake inhibitors (SSRIs) might theoretically reduce post-stroke disability by direct effects on the brain. This Cochrane Review was first published in 2012 and last updated in 2019.

Objectives: To determine if SSRIs are more effective than placebo or usual care at improving outcomes in people less than 12 months post-stroke, and to determine whether treatment with SSRIs is associated with adverse effects.

Search methods: We searched the Cochrane Stroke Group Trials Register (last searched 7 January 2021), Cochrane Controlled Trials Register (CENTRAL, Issue 7 of 12, 7 January 2021), MEDLINE (1946 to 7 January 2021), Embase (1974 to 7 January 2021), CINAHL (1982 to 7 January 2021), PsycINFO (1985 to 7 January 2021), and AMED (1985 to 7 January 2021). PsycBITE had previously been searched (16 July 2018). We searched clinical trials registers.

Selection criteria: We included randomised controlled trials (RCTs) recruiting stroke survivors within the first year. The intervention was any SSRI, at any dose, for any period, and for any indication. The comparator was usual care or placebo. Studies reporting at least one of our primary (disability score or independence) or secondary outcomes (impairments, depression, anxiety, quality of life, fatigue, cognition, healthcare cost, death, adverse events and leaving the study early) were included in the meta-analysis. The primary analysis included studies at low risk of bias.

Data collection and analysis: We extracted data on demographics, stroke type and, our pre-specified outcomes, and bias sources. Two review authors independently extracted data. We used mean difference (MD) or standardised mean differences (SMDs) for continuous variables, and risk ratios (RRs) for dichotomous variables, with 95% confidence intervals (CIs). We assessed bias risks and applied GRADE criteria.

Main results: We identified 76 eligible studies (13,029 participants); 75 provided data at end of treatment, and of these two provided data at follow-up. Thirty-eight required participants to have depression to enter. The duration, drug, and dose varied. Six studies were at low risk of bias across all domains; all six studies did not need participants to have depression to enter, and all used fluoxetine. Of these six studies, there was little to no difference in disability between groups SMD -0.0; 95% CI -0.05 to 0.05; 5 studies, 5436 participants, high-quality evidence) or in independence (RR 0.98; 95% CI 0.93 to 1.03; 5 studies, 5926 participants; high-quality evidence) at the end of treatment. In the studies at low risk of bias across all domains, SSRIs slightly reduced the average depression score (SMD 0.14 lower, 95% CI 0.19 lower to 0.08 lower; 4 studies; 5356 participants, high-quality evidence) and there was a slight reduction in the proportion with depression (RR 0.75, 95% CI 0.65 to 0.86; 3 studies, 5907 participants, high-quality evidence). Cognition was slightly better in the control group (MD -1.22, 95% CI -2.37 to -0.07; 4 studies, 5373 participants, moderate-quality evidence). Only one study (n = 30) reported neurological deficit score (SMD -0.39, 95% CI -1.12 to 0.33; low-quality evidence). SSRIs resulted in little to no difference in motor deficit (SMD 0.03, -0.02 to 0.08; 6 studies, 5518 participants, moderate-quality evidence). SSRIs slightly increased the proportion leaving the study early (RR 1.57, 95% CI 1.03 to 2.40; 6 studies, 6090 participants, high-quality evidence). SSRIs slightly increased the outcome of a seizure (RR 1.40, 95% CI 1.00 to 1.98; 6 studies, 6080 participants, moderate-quality evidence) and a bone fracture (RR 2.35, 95% CI 1.62 to 3.41; 6 studies, 6080 participants, high-quality evidence). One study at low risk of bias across all domains reported gastrointestinal side effects (RR 1.71, 95% CI 0.33, to 8.83; 1 study, 30 participants). There was no difference in the total number of deaths between SSRI and placebo (RR 1.01, 95% CI 0.82 to 1.24; 6 studies, 6090 participants, moderate quality evidence). SSRIs probably result in little to no difference in fatigue (MD -0.06; 95% CI -1.24 to 1.11; 4 studies, 5524 participants, moderate-quality of evidence), nor in quality of life (MD 0.00; 95% CI -0.02 to 0.02, 3 studies, 5482 participants, high-quality evidence). When all studies, irrespective of risk of bias, were included, SSRIs reduced disability scores but not the proportion independent. There was insufficient data to perform a meta-analysis of outcomes at end of follow-up. Several small ongoing studies are unlikely to alter conclusions.

Authors' conclusions: There is high-quality evidence that SSRIs do not make a difference to disability or independence after stroke compared to placebo or usual care, reduced the risk of future depression, increased bone fractures and probably increased seizure risk.

Trial registration: ClinicalTrials.gov NCT02683213.

PubMed Disclaimer

Conflict of interest statement

Lynn A Legg: none known.

Ann‐Sofie Rudberg: none known.

Xing Hua: none known.

Simiao Wu: none known.

Maree L Hackett: Grants and contracts: Project grant (NHMRC funding for AFFINITY trial), HTA Program (National Institute for Health Research funding for FOCUS), Framework grant (Swedish Research Council funding for EFFECTS); all funding received by the author's institution. Payment for a fellowship: National Health and Medical Research Council (NHMRC), received by the author's institution.

Russel Tilney: none known.

Linnea Lindgren: none known.

Mansur A Kutlubaev: none known.

Cheng‐Fang Hsieh: none known.

Amanda Barugh: none known.

Graeme J Hankey: Grants and contracts: Chief Investigator for the AFFINITY trial, National Health and Medical Research Council of Australia, received by the author's institution. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events: Discussion about antithrombotic therapy to prevent stroke, Medscape, received by the author. Consulting fees: Consulting on design of a possible phase III trial of a new anticoagulant in atrial fibrillation, Janssen Research and Development, received by the author. Payment for participation on a Data Safety Monitoring Board, Advisory Board, or Guideline Panel: Chair or Member of Data Safety Monitoring Committees, of ACI trials of an immune therapies for Alzheimer's disease, AC Immune, Lausanne, Switzerland, received by the author; Member of Stroke Prevention Initiative, Bayer, received by the author; Other: Associate Editor of Circulation, American Heart Association, received by the author. Published opinions in medical journals, the public press, broadcast and social media relevant to the interventions in the work: Publication, Lancet Neurology, AFFINITY Trial Collaboration. Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double‐blind, placebo‐controlled trial. Lancet Neurology 2020; 19(8): 651‐660. doi: 10.1016/S1474‐4422(20)30207‐6. PMID: 32702334; Publication, Stroke. Declaring involvement in eligible studies: Yes, National Health and Medical Research Council of Australia (for AFFINITY trial).

Erik Lundström: Grants and contracts: Funding, STROKE‐Riksförbundet, received by author's institution. Leadership or other fiduciary role in other board, society, committee, or advocacy group: Chief Investigator of the EFFECTS trial, received by author. Declaring involvement in eligible studies: The Swedish Research Council, The Swedish Heart‐Lung Fund, The Swedish Brain Fund, STROKE‐Riksförbundet, The Swedish Medical Society, Konung Gustaf V:s och Drottning Victorias Frimurarstiftelse.

Martin Dennis: Grants and contracts: Grants received to carry out FOCUS trial ‐ and RCT which is included in the review, NIHR, Stroke Association, received by the author's institution

Gillian E Mead: Grants and contracts: Research grants, HTA NIHR, co‐applicant on grants led by Prof Graeme Hankey and Maree Hackett, and Erik Lundstrom; NIHR incentive award for updating this review, both received by the author's institution.

Gillian Mead, Martin Dennis, Maree Hackett, Erik Lundstrom and Graeme Hankey are investigators on the FOCUS trial (Fluoxetine or control under supervision) in the UK, the AFFINITY (Assessment of fluoxetine in stroke recovery) trial in Australia, and the EFFECTs trial in Sweden designed to assess the impact of fluoxetine on disability and dependency after stroke. None of these review authors extracted data from these three trials.

Figures

1
1
PRISMA flow diagram for this update
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
'Risk of bias' graph: review authors' judgements about each 'risk of bias' item presented as percentages across all included studies.
4
4
Funnel plot, all studies irrespective or risk of bias, for disability at end of treatment.
1.1
1.1. Analysis
Comparison 1: SSRI versus control at end of treatment, by SSRI, Outcome 1: Disability (primary outcome). Studies at low risk of bias
1.2
1.2. Analysis
Comparison 1: SSRI versus control at end of treatment, by SSRI, Outcome 2: Independent on modified Rankin score (mRS 0 to 2) (primary outcome). Studies at low risk of bias
1.3
1.3. Analysis
Comparison 1: SSRI versus control at end of treatment, by SSRI, Outcome 3: Neurological deficit score (studies at low risk of bias)
1.4
1.4. Analysis
Comparison 1: SSRI versus control at end of treatment, by SSRI, Outcome 4: Motor deficits (studies at low risk of bias)
1.5
1.5. Analysis
Comparison 1: SSRI versus control at end of treatment, by SSRI, Outcome 5: Depression, continuous data (studies at low risk of bias)
1.6
1.6. Analysis
Comparison 1: SSRI versus control at end of treatment, by SSRI, Outcome 6: Depression, dichotomous data (studies at low risk of bias)
1.7
1.7. Analysis
Comparison 1: SSRI versus control at end of treatment, by SSRI, Outcome 7: Death (trials at low risk of bias)
1.8
1.8. Analysis
Comparison 1: SSRI versus control at end of treatment, by SSRI, Outcome 8: Seizures (studies at low risk of bias)
1.9
1.9. Analysis
Comparison 1: SSRI versus control at end of treatment, by SSRI, Outcome 9: Gastrointestinal side effects (studies at low risk of bias)
1.10
1.10. Analysis
Comparison 1: SSRI versus control at end of treatment, by SSRI, Outcome 10: Bleeding (studies at low risk of bias)
1.11
1.11. Analysis
Comparison 1: SSRI versus control at end of treatment, by SSRI, Outcome 11: Fractures (studies at low risk of only)
1.12
1.12. Analysis
Comparison 1: SSRI versus control at end of treatment, by SSRI, Outcome 12: Cognition (trials at low risk of bias)
1.13
1.13. Analysis
Comparison 1: SSRI versus control at end of treatment, by SSRI, Outcome 13: Leaving the study before the end of scheduled follow‐up for reasons other than death (trials at low risk of bias)
1.14
1.14. Analysis
Comparison 1: SSRI versus control at end of treatment, by SSRI, Outcome 14: Fatigue at end of treatment (studies at low risk of bias only)
1.15
1.15. Analysis
Comparison 1: SSRI versus control at end of treatment, by SSRI, Outcome 15: Quality of life at end of treatment (studies at low risk of bias)
1.16
1.16. Analysis
Comparison 1: SSRI versus control at end of treatment, by SSRI, Outcome 16: Disability (all studies regardless of risk of bias)
1.17
1.17. Analysis
Comparison 1: SSRI versus control at end of treatment, by SSRI, Outcome 17: Independent on modified Rankin score (mRS 0 to 2) (all studies regardless of risk of bias)
2.1
2.1. Analysis
Comparison 2: SSRI versus control at end of follow up, by SSRI, Outcome 1: Disability (studies at low risk of bias only)
2.2
2.2. Analysis
Comparison 2: SSRI versus control at end of follow up, by SSRI, Outcome 2: Independent on modified rankin score (0‐2) (studies at low risk of bias only)
2.3
2.3. Analysis
Comparison 2: SSRI versus control at end of follow up, by SSRI, Outcome 3: Depression, continuous data (studies at low risk of bias only)
2.4
2.4. Analysis
Comparison 2: SSRI versus control at end of follow up, by SSRI, Outcome 4: Depression, dichotomous (studies at low risk of bias only)
2.5
2.5. Analysis
Comparison 2: SSRI versus control at end of follow up, by SSRI, Outcome 5: Motor deficits (studies at low risk of bias only)
2.6
2.6. Analysis
Comparison 2: SSRI versus control at end of follow up, by SSRI, Outcome 6: Cognition (studies at low risk of bias only)
2.7
2.7. Analysis
Comparison 2: SSRI versus control at end of follow up, by SSRI, Outcome 7: Death (studies at low risk of bias only)
2.8
2.8. Analysis
Comparison 2: SSRI versus control at end of follow up, by SSRI, Outcome 8: Leaving the trial before the end of follow‐up, for reasons other than death ( studies at low risk of bias)
2.9
2.9. Analysis
Comparison 2: SSRI versus control at end of follow up, by SSRI, Outcome 9: Disability, all studies irrespective of risk of bias
2.10
2.10. Analysis
Comparison 2: SSRI versus control at end of follow up, by SSRI, Outcome 10: Independent on mRS (0‐2) all studies irrespective of risk of bias
See this image and copyright information in PMC

Update of

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Kim 2017 {published data only}
    1. Kim JS, Lee E-J, Chang D-ll, Park J-H, Ahn SH, Cha J-K, et al. Efficacy of early administration of escitalopram on depressive and emotional symptoms and neurological dysfunction after stroke: a multicentre, double-blind, randomised, placebo-controlled study. Lancet Psychiatry 2017;4(1):33-41. - PubMed
    1. Lee EJ, Kim JS, Chang DI, Park JH, Ahn SH, Cha JK, et al. Differences in therapeutic responses and factors affecting post-stroke depression at a later stage according to baseline depression. Journal of Stroke 2018;20(2):258-67. - PMC - PubMed
    1. Lee EJ, Kim JS, Chang DI, Park JH, Ahn SH, Cha JK, et al. Post-stroke depressive symptoms: varying responses to escitalopram by individual symptoms and lesion location. Journal of Geriatric Psychiatry and Neurology 2020;10:891988720957108. - PubMed
    1. Lee EJ, Oh MS, Kim JS, Chang DI, Park JH, Cha JK, EMOTION investigators. Serotonin transporter gene polymorphisms may be associated with poststroke neurological recovery after escitalopram use. Journal of Neurology, Neurosurgery and Psychiatry 2018;89(3):271-6. - PubMed
    1. NCT01278498. The preventative effect of escitalopram on depression and related emotional disorders in acute stroke patients, 2011. clinicaltrials.gov/ct2/show/NCT01278498 (first received 19 January 2011). [NCT01278498]
Kong 2007 {published data only}
    1. Kong Y. Fluoxetine for poststroke depression: a randomized placebo controlled clinical trial. Neural Regeneration Research 2007;2(3):162-5.
Lai 2006 {published data only}
    1. Lai J. The effect of using paroxetine to treat post stroke depression. Journal of Guangdong Medical College 2006;24(6):585-6.
Li 2004a {published data only}
    1. Li J, He Q-Y, Han M-F. Recent effect of fluoxetine in improving neurologic impairment and preventing post-stroke depression in the early stage. Chinese Journal of Clinical Rehabilitation 2004;8(7):1208-9.
Li 2004b {published data only}
    1. Li C-M, Jiang X-D, Liao G, Lei J-M, Lan S, Ni F-W. Effect of antidepressant drugs in early period on the recovery of post-stroke depression. Chinese Journal of Clinical Rehabilitation 2004;8(19):3713-5.
Li 2005 {published data only}
    1. Li Y, Wang X, Qian FS. Related factors of post-stroke depression and effect of paroxetine. Shandong Archives of Psychiatry 2005;18(4):209-10.
Li 2006 {published data only}
    1. Li W-Q, Li D-X. The efficacy of citalopram for post-stroke depression and its effects on stroke rehabilitation. International Journal of Cerebrovascular Diseases 2006;14(4):275-8.
Li 2007 {published data only}
    1. Li Z. Clinical efficacy of paroxetine in the treatment of post-stroke depression. Modern Journal of Integrated Traditional Chinese and Western Medicine 2007;16(34):5103-4.
Li 2008 {published data only}
    1. Li L-T, Wang S-H, Ge H-Y, Chen J, Yue S-W, Yu M. The beneficial effects of the herbal medicine free and easy wanderer plus (FEWP) and fluoxetine on post-stroke depression. Journal of Alternative and Complementary Medicine 2008;14(7):841-6. - PubMed
Li 2017 {published data only}
    1. Li J, Wang J, Li Y, Zhang W, Zhao J. Effects of escitalopram oxalate on post-stroke depression, cognition and neurological function. Journal of Hebei Medical University 2017;38(5):589-92.
Liu 2006 {published data only}
    1. Liu Y, Xu R. Effect of citalopram treatment on post-stroke depression and neurological functional rehabilitation. Chinese Journal of Rehabilitation 2006;21(3):174-5.
Marquez Romero 2013 {published data only}
    1. Marquez-Romero JM, Arauz A, Ruiz-Sandoval JL, Cruz-Estrada Ede L, Huerta-Franco MR, Aguayo-Leytte G, et al. Fluoxetine for motor recovery after acute intracerebral hemorrhage (FMRICH): study protocol for a randomized, double-blind, placebo-controlled, multicenter trial. Trials 2013;14:77. - PMC - PubMed
    1. Marquez-Romero JM, Reyes-Martínez M, Huerta-Franco MR, Ruiz-Franco A, Silos H, Arauz A. Fluoxetine for motor recovery after acute intracerebral hemorrhage, the FMRICH trial. Clinical Neurology and Neurosurgery 2020;190:105656. - PubMed
    1. Marquez-Romero JM, Reyes-Martínez M, Huerta-Franco MR, Ruiz-Franco A, Silos H, Arauz A. Fluoxetine for motor recovery after acute intracerebral hemorrhage, the FMRICH Trial. Correspondence from Marquez-Romero 2018. - PubMed
    1. Marquez-Romero JM. Fluoxetine for motor recovery after acute intracerebral hemorrhage (FMRICH). www.clinicaltrials.gov/ct2/show/NCT01737541 (first received 29 November 2012).
Meara 1998 {published data only}
    1. Meara RJ, Thalanany M, Balonwu V, Hobson P. The treatment of depression after stroke with the selective serotonin reuptake inhibitor sertraline. Cerebrovascular Diseases 1998;8 Suppl 4:90.
Miao 2004 {published data only}
    1. Miao S-Y, Shi Y-J. Related factors of post-stroke depression and therapeutical effect of citalopram. Chinese Journal of Clinical Rehabilitation 2004;8(19):3718-9.
Murray 2005 {published data only}
    1. Murray V, Von Arbin M, Bartfai A, Berggren A-L, Landtblom A-M, Lumdmark J, et al. Double-blind comparison of sertraline and placebo in stroke patients with minor depression and less severe major depression. Journal of Clinical Psychiatry 2005;66(6):708-16. - PubMed
NCT00177424 {published data only}
    1. NCT00177424. Setraline for prevention post stroke depression and improving rehabilitation outcomes. clinicaltrials.gov/ct2/show/NCT00177424 (first received 15 September 2005).
NCT01674868 {published data only}
    1. NCT01674868. Fluoxetine for motor, aphasia, and neglect recovery after ischemic stroke (FLAN). www.clinicaltrials.gov/ct2/show/NCT01674868 (first received 29 August 2012).
NCT02737930 {published data only}
    1. NCT02737930. Fluoxetine for visual recovery after ischaemic stroke (FLUORESCE). www.clinicaltrials.gov/ct2/show/NCT02737930 (first received 14 April 2016).
Pan 2018 {published data only}
    1. Pan X-L, Chen H-F, Cheng X, Hu C-C, Wang J-W, Fu Y-M, et al. Effects of paroxetine on motor and cognitive function recovery in patients with non-depressed ischemic stroke: an open randomized controlled study. Brain Impairment;doi: 10.1017/BrImp.2018.6.
Pariente 2001 {published data only}
    1. Guiraud-Chaumeil B, Pariente J, Albucher J-F, Loubinoux I, Chollet F. Rehabilitation after stroke [Recuperation neurologique post-ischemique]. Bulletin de l'Académie Nationale de Médecine 2002;6:1015-24. - PubMed
    1. Pariente J, Loubinoux I, Carel C, Albucher JF, Leger A, Manelfe C, et al. Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke. Annals of Neurology 2001;50(6):718-29. - PubMed
Rasmussen 2003 {published data only}
    1. Rasmussen A, Lunde M, Poulsen D, Sørensen K, Qvitzau S, Bech P. A double-blind placebo controlled study of sertraline in the prevention of depression in stroke patients. European Neuropyschopharmacology 2002;12:231. - PubMed
    1. Rasmussen A, Lunde M, Poulsen DL, Sørensen K, Qvitzau S, Bech P. A double-blind, placebo-controlled study of sertraline in the prevention of depression in stroke patients. Psychosomatics 2003;44(3):216-22. - PubMed
    1. Rasmussen A. Depression and stroke. Nordic Journal of Psychiatry 2001;55(4):288.
    1. Rasmussen A. Prophylactic treatment for post-stroke depression and comorbidity. Journal of Psychosomatic Research 2000;48(3):66.
Razazian 2014 {published data only}
    1. Razazian N, Esmaeili O, Almasi A. Effect of fluoxetine on motor improvement in ischemic stroke patients: a double blind clinical trial study. Zahedan Journal of Research in Medical Sciences 2016;18(7):e75492016.
    1. Razazian N. A survey for assessment of effectiveness of fluoxetine on motor improvement in ischemic stroke patients. www.en.irct.ir/trial/8797 (first received 9 January 2014).
Restifo 2001 {published data only}
    1. Restifo DA, Lo Prest R, Lanza S, Giuffrida S, D'Aleo G, Rifici Di Bella C, et al. Motor cortex reorganization induced by fluoxetine in poststroke hemiplegic patients undergoing rehabilitation therapy: a study with transcranial magnetic stimulation. Neurorehabilitation and Neural Repair 2001;15(4):284.
Robinson 2000a {published data only}
    1. Jorge RE, Robinson RG, Arndt S, Starkstein S. Mortality and post-stroke depression: a placebo controlled trial of antidepressants. American Journal of Psychiatry 2003;160:1823-9. - PubMed
    1. Narushima K, Kosier JT, Robinson RG. Preventing post-stroke depression: a 12 week double blind randomised treatment trial and 21 month follow-up. Journal of Nervous and Mental Diseases 2002;190:296-303. - PubMed
    1. Robinson RG, Schultz SK, Castillo C, Kopel T, Kosier JT, Newman RM, et al. Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebo-controlled, double-blind study. American Journal of Psychiatry 2000;157(3):351-9. - PubMed
Robinson 2000b {published data only}
    1. Jorge RE, Robinson RG, Arndt S, Starkstein S. Mortality and post-stroke depression: a placebo controlled trial of antidepressants. American Journal of Psychiatry 2003;160:1823-9. - PubMed
    1. Narushima K, Robinson RG. Preventing post-stroke depression: a 12 week double blind randomised treatment trial and 21 month follow-up. Journal of Nervous and Mental Diseases 2002;190:296-303. - PubMed
    1. Robinson RG, Schultz SK, Castillo C, Kopel T, Kosier JT, Newman RM, et al. Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebo-controlled, double-blind study. American Journal of Psychiatry 2000;157(3):351-9. - PubMed
Robinson 2008 {published data only}
    1. Jorge RE, Acion L, Moser D, Adams HP, Robinson RG. Escitalopram and enhancement of cognitive recovery following stroke. Archives of General Psychiatry 2010;67(2):187-96. - PMC - PubMed
    1. Robinson RG, Arndt S. Incomplete financial disclosure in a study of escitalopram and problem solving therapy for prevention of post-stroke depression. JAMA 2009;301:1023-4. - PubMed
    1. Robinson RG, Jorge RE, Moser DJ, Acion L, Solodkin A, Small SL, et al. Escitalopram and problem-solving therapy for prevention of poststroke depression. JAMA 2008;299(20):2391-400. - PMC - PubMed
Savadi Oskouie 2012 {published data only}
    1. Savadi Oskouie D, Sharifipour E, Sadeghi Bazargani H, Hashemilar M, Nikanfar M, Ghazanfari Amlashi S, et al. Efficacy of citalopram on acute ischemic stroke outcome: a randomized clinical trial. Neurorehabilitation and Neural Repair 2017;31(7):638-47. - PubMed
    1. Savadi Oskouie D. Evaluation of the effect of citalopram on three months functional prognosis of acute ischemic stroke patients: a randomized clinical trial. www.en.irct.ir/trial/1766 (first received 22 April 2012).
Shah 2016 {published data only}
    1. Shah IA, Asimi RP, Kawoos Y, Wani MA, Wani MA, Dar MA. Effect of fluoxetine on motor recovery after acute haemorrhagic stroke: a randomized trial. Journal of Neurology and Neurophysiology 2016;7(2). [DOI: 10.4172/2155-9562.1000364] - DOI
Song 2006 {published data only}
    1. Song J-G. Effects of fluoxetine hydrochloride on depressive symptoms and P300 after cerebral stroke. Chinese Journal of Clinical Rehabilitation 2006;10(14):160-2.
Wang 2003 {published data only}
    1. Wang X, Tan Z, Wu Z, Gao J, Feng M. The effects of anti-depression therapy on post-stroke depression and neurologic rehabilitation in the elderly patients. Chinese Journal of Geriatrics 2003;22(5):270-3.
Wang 2009 {published data only}
    1. Wang X. The efficacy of paroxetine in the treatment of post-stroke depression in 55 cases. Chinese Community Physician (Medical Professional Half-monthly) 2009;11(7):11.
Wen 2006 {published data only}
    1. Wen Z-X. The influence of post-stroke prophylactic anti-depression treatment on nerve functional rehabilitation. Acta Academiae Medicinae Qingdao Universitatis 2006;42(3):253-4.
Wiart 2000 {published data only}
    1. Wiart L, Petit H, Joseph PA, Mazaux JM, Barat M. Fluoxetine in early poststroke depression: a double-blind placebo-controlled study. Stroke 2000;31(8):1829-32. - PubMed
Xie 2005 {published data only}
    1. Xie R, Liu J, Quan H. A prospective random clinical contrast study of treatment with sertraline in elderly patients with post-stroke depression. Chinese Journal of Clinical Neuroscience 2005;13(3):294-7.
Xu 2001 {published data only}
    1. Xu J, Tan J, Ou L. A study on treatment of fluoxetine to depression in early recovery stage of cerebral infarction. Chinese Journal of Rehabilitation Medicine 2001;16(5):281-3.
Xu 2006 {published data only}
    1. Xu J, Wang J, Liu J. Preventive effects of antidepressants on post-stroke depression. Chinese Mental Health Journal 2006;20(3):186-8.
Yang 2002 {published data only}
    1. Yang J, Zhao Y, Bai S. Controlled study on antidepressant treatment of patients with post-stroke depression. Chinese Mental Health Journal 2002;16(12):871-2.
Yang 2011 {published data only}
    1. Yang J. Therapeutic effect of paroxetine on patients with early poststroke depression and the serum interleukins. Chinese Journal of Cerebrovascular Diseases 2011;8(5):235-8.
Ye 2004 {published data only}
    1. Ye L-X, Wang H, Wang Y-D, Zhong L, Liang D-S, Guo Y. Effect of anti-depressive therapy on the rehabilitation of psychological and neurological function after stroke. Chinese Journal of Clinical Rehabilitation 2004;8(31):6826-8.
    1. Ye LX. Effect of paxil and berhomine on post-stroke anxiety-depression and neurological recovery. Chinese Journal of Clinical Rehabilitation 2006;10(6):153-5.
Zhao 2011 {published data only}
    1. Zhao P, Wang J-P. Effects of antidepressants on neurofunctional recovery of post-stroke patients with aphasia. Journal of Dalian Medical University 2011;33(1):55-7.
Zhou 2008 {published data only}
    1. Zhou Z-l, Liang L-Z, Yan Y-X. Preventive effects of fluoxetine on post-stroke depression. Chinese Journal of Modern Applied Pharmacy 2008;25(3):263-4.

References to studies excluded from this review

ACTRN12619000573156 {published data only}
    1. ACTRN12619000573156. FRAMBOISE: Fluoxetine, Recovery And Motor BiOmarkers In StrokE. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377306 (first received 11 April 2019).
Andersen 1993 {published data only}
    1. Andersen G, Vestergaard K, Riis JO. Citalopram for post-stroke pathological crying. Lancet 1993;342(8875):837-9. - PubMed
Andersen 2012 {published data only}
    1. Andersen G. Efficacy of escitalopram treatment in acute stroke and the role of specific genotypes in stroke. www.clinicaltrialsregister.eu/ctr-search/search?query=2011-005541-12 (first received 27 February 2012).
    1. Andersen G. Escitalopram Treatment In Acute Stroke (ESTIAS). www.clinicaltrials.gov/ct2/show/NCT01561092 (first received 22 March 2012).
Anderson 2002 {published data only}
    1. Anderson C, Hackett M, Carter K, Ni MC. Maximising outcome by overcoming depression in stroke (MOODS) trial. Cerebrovascular Diseases 2002 2002;13 Suppl 3:79.
Anonymous 2012a {published data only}
    1. Anonymous 2012. Stroke and depression. Johns Hopkins Medical Letter: Health After 50 2012;23(11):3. - PubMed
Anonymous 2012b {published data only}
    1. Anonymous. Drug & Device News. Medical Malpractice Law & Strategy, New York Law Journal Newsletters 2012;30(2):5.
Berends 2009 {published data only}
    1. Berends HI, Nijlant JM, Putten MJ, Movig KL, IJzerman MJ. Single dose of fluoxetine increases muscle activation in chronic stroke patients. Clinical Neuropharmacology 2009;32(1):1-5. [also known as Flu 2006] - PubMed
Bonin Pinto 2019 {published data only}
    1. Bonin Pinto C, Morales-Quezada L, Toledo Piza PV, Zeng D, Saleh Vélez FG, Ferreira IS, et al. Combining fluoxetine and rTMS in poststroke motor recovery: a placebo-controlled double-blind randomized phase 2 clinical trial. Neurorehabilitation and Neural Repair 2019;33:643-55. [DOI: 10.1177/1545968319860483.] - DOI - PMC - PubMed
    1. NCT02208466. Effects rTMS combined with fluoxetine on motor recovery in stroke patients. www.clinicaltrials.gov/ct2/show/NCT02208466 (first received 5 August 2014).
Chen 2019 {published data only}
    1. Chen Ma, Ping L. Effectiveness of paroxetine in the treatment of poststroke depression. Medicine 2018;97(29):1-4. - PMC - PubMed
Choi Kwon 2008 {published data only}
    1. Choi-Kwon S, Choi J, Kwon SU, Kang DW, Kim JS. Fluoxetine improves the quality of life in patients with poststroke emotional disturbances. Cerebrovascular Diseases 2008;26(3):266-71. - PubMed
Finkenzeller 2009 {published data only}
    1. Finkenzeller W, Zobel I, Rietz S, Schramm E, Berger M. Interpersonal psychotherapy and pharmacotherapy for post-stroke depression. Feasibility and effectiveness. Der Nervenarzt 2009;80(7):805-12. - PubMed
Foster 2019 {published data only}
    1. Foster E, Yaroslavtseva O, Chundamala J, Leibovitch F, Eng JJ, Ali F, et al. FLOW Trial: fluoxetine to open the critical period time window to improve motor recovery after stroke. International Journal of Stroke 2019;14 Suppl 3:36.
Gourab 2015 {published data only}
    1. Gourab K, Schmit BD, Hornby GT. Increased lower limb spasticity but not strength or function following a single-dose serotonin reuptake inhibitor in chronic stroke. Archives of Physical Medicine and Rehabilitation 2015;96(12):2112-9. - PubMed
Graffagnino 2002 {published data only}
    1. Graffagnino C. Poststroke depression and functional recovery (SADBRAIN). Duke University Medical Centre 2002.
Ji 2000 {published data only}
    1. Ji QM, Xie LP. Efficacy of fluoxetine in the treatment of 20 patients with depression after stroke. Herald of Medicine 2000;19(4):329.
Kitago 2020 {published data only}
    1. Dose-finding study of selective serotonin reuptake inhibitors to enhance neuroplasticity [Dose finding study but the intervention is a combination of an SSRI and paired associative stimulation, so we can exclude]. Source not provided from searches 2020.
Li 2002 {published data only}
    1. Li F, Gu DX, Ceng SH, Xu JW. Effect of paroxetine on prognosis of patients with post cerebral infarction depression. Chinese Journal of New Drugs and Clinical Remedies. 2002;21(1):11-3.
Liang 2003 {published data only}
    1. Liang Z, Shuliang T. Clinical efficacy of fluoxetine in treatment of patients with depression after acute stroke. Chinese Journal of Clinical Rehabilitation 2003;7(13):1924-5.
Liu 2004 {published data only}
    1. Liu L-X. Recent effect of drug intervention on post-stroke anxiety. Chinese Journal of Clinical Rehabilitation 2004;8(30):6600-1.
Liu 2020 {published data only}
    1. Liu W, Ding W. Study on the efficacy and mechanism of paroxetine hydrochloride combined with repetitive transcranial magnetic stimulation in the treatment of post-stroke depression. International Journal of Clinical and Experimental Medicine 2020;13(10):7881-8.
Mosarrezaii 2018 {published data only}
    1. Mosarrezaii A, Salmasi BA, Taghavi SA. Studying effect of fluoxetine on improvement of motor performance in patients with ischemic stroke. Journal of Research in Medical and Dental Sciences 2018;6(3):118-22.
NCT01963832 {published data only}
    1. NCT01963832. RCT of a neuroplasticity agent and CI therapy for severe arm paresis after stroke. clinicaltrials.gov/ct2/show/NCT01963832 (first received 16 October 2013).
Robinson 2011 {published data only}
    1. Robinson RG, Mikami K, Jang M, Jorge RE. Prevention of anxiety disorder after stroke. Journal of Neuropsychiatry and Clinical Neurosciences 2011;23(2):18.
Sitzer 2002 {published data only}
    1. Sitzer M, Huff W, Steckel R. Prevention of poststroke depression after acute ischemic stroke using the selective serotonin reuptake inhibitor sertraline (PreDis-study). Stroke 2002;33(2):651-2.
Sun 2015 {published data only}
    1. Sun YT, Bao YH, Wang SL, Chu JM, Li LP. Efficacy observation on the treatment of post-stroke depression by acupuncture at the acupoints based on ziwuliuzhu and Prozac. Chinese Acupuncture and Moxibustion 2015;355(2):119-22. - PubMed
Vogel 2020 {published data only}
    1. Vogel AC, Okeng'o K, Chiwanga F, Ismail SS, Buma D, Pothier L. MAMBO: Measuring Ambulation, Motor, and Behavioral Outcomes with post-stroke fluoxetine in Tanzania: protocol of a phase II clinical trial. Journal of the Neurological Sciences 2020;408:116563. [PMID: ] - PMC - PubMed
Xu 2007 {published data only}
    1. Xu B, Zhou WY, Zhang SJ. Observation of effect of Wulung capsule in treating post-stroke depression. Chinese Journal of Integrated Traditional and Western Medicine 2007;27(7):640-2. - PubMed
Zhou 2003 {published data only}
    1. Zhou B. Effects of fluoxetine on neurofunctional recovery of non depressed patients after stroke. Chinese Journal of Clinical Rehabilitation 2003;7(3):374-5.

References to studies awaiting assessment

Guo 2016 {published data only}
    1. Guo Y, He Y, Tang B, Ma K, Cai Z, Zeng S, et al. Effect of using fluoxetine at different time windows on neurological functional prognosis after ischemic stroke. Restorative Neurology and Neuroscience 2016;34(2):177–87. - PubMed
    1. Guo Y. Effect of using fluoxetine at different time windows after ischemic stroke on neurological functional prognosis: a randomized controlled trial. chictr.org.cn/showprojen.aspx?proj=12925 (first received 27 December 2015).
He 2018 {published data only}
    1. ChiCTR-TRC-12002078. Multi-center randomized clinical study of antidepressant treatment (fluoxetine) on secondary prevention of ischemic stroke. www.chictr.org.cn/showprojen.aspx?proj=7471 (first received 3 April 2012).
    1. He Y, Cai Z, Zeng S, Chen S, Tang B, Liang Y, et al. Effect of fluoxetine on three-year recurrence in acute ischemic stroke: a randomized controlled clinical study. Clinical Neurology and Neurosurgery 2018;168:1-6. - PubMed
Jurcau 2016 {published data only}
    1. Jurcau A, Simion A. Improved post-ischaemic stroke recovery over 1 year with escitalopram for 3 months. European Journal of Neurology 2016;23:614.
NCT00967408 {published data only}
    1. NCT00967408. Effects of clinical and functional outcome of escitalopram in adult stroke patients. clinicaltrials.gov/ct2/show/NCT00967408 (first received 27 August 2009). [NCT00967408]

References to ongoing studies

ChiCTR1800019467 {published data only}
    1. ChiCTR1800019467. The effect and mechanism of fluoxetine on the automatic regulation of cerebral blood flow for ischemic stroke. https://www.chictr.org.cn/showprojen.aspx?proj=32801.
CTRI/2018/12/016568 {published data only}
    1. CTRI/2018/12/016568. An interventional study to look at efficacy of fluoxetine in patients with post-stroke anxiety. http://ctri.nic.in CTRI/2018/12/016568 (first received 10 December 2018).
EudraCT 2005‐005266‐37 {published data only}2005‐005266‐37
    1. EudraCT 2005-005266-37. Influence of escitalopram on the incidence of depression and dementia following acute middle cerebral artery territory infarction. A randomised placebo-controlled double blind study. www.clinicaltrialsregister.eu/ctr-search/search?query=2005-005266-37 (first received 7 April 2006).
IRCT201112228490N1 {published data only}
    1. IRCT201112228490N1. Effect of fluoxetine on functional recovery of patients with cerebrovascular accident following middle cerebral artery trunk obstruction: a randomized clinical trial. www.en.irct.ir/trial/8954 (first received 25 January 2012).
IRCT2012101011062N1 {published data only}
    1. IRCT2012101011062N1. A study of sertraline effect on quality of life in stroke inpatients. www.en.irct.ir/trial/11413 (first received 28 November 2012).
IRCT2017041720258N37 {published data only}
    1. IRCT2017041720258N37. Evaluation of fluoxetine and standard treatment efficacy on change to side effect of stroke of ischemic strokes in both hemispheres in anterior circulation. www.irct.ir/trial/17976 (first received 11 October 2017).
IRCT20210307050617N1 {published data only}
    1. IRCT20210307050617N1. The efficacy comparison of fluoxetine and citalopram on motor recovery after ischemic stroke: single-blind placebo-controlled randomized clinical trial. https://en.irct.ir/trial/54896 (first received 27 March 2021).
NCT02386475 {published data only}
    1. NCT02386475. Effect of serotonin and levodopa in ischemic stroke. www.clinicaltrials.gov/ct2/show/NCT02386475 (first received 12 March 2015).
NCT02767999 {published data only}
    1. NCT02767999. Serotonin Selective Reuptake Inhibitor (SSRI) effects on cerebral connectivity in acute ischemic stroke (RECONISE). www.clinicaltrials.gov/ct2/show/NCT02767999 (first received 11 May 2016).
NCT02865642 {published data only}
    1. NCT02865642. Cortical ischemic stroke and serotonin (CISS). www.clinicaltrials.gov/ct2/show/NCT02865642 (first received 12 August 2016).
NCT03448159 {published data only}
    1. NCT03448159. Fluoxetine Opens Window to improve motor recovery after stroke (FLOW). www.clinicaltrials.gov/ct2/show/NCT03448159 (first received 27 February 2018).
NCT03826875 {published data only}
    1. NCT03826875. Depression in hemorrhagic stroke. www.clinicaltrials.gov/ct2/show/NCT03826875 (first received 1 February 2019).
TCTR20181216001 {published data only}
    1. TCTR20181216001. Randomized controlled trial of fluoxetine or placebo on quality of life after acute ischemic stroke. www.thaiclinicaltrials.org/show/TCTR20181216001 (first received 16 December 2018).

Additional references

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References to other published versions of this review

Legg 22019
    1. Legg LA, Tilney R, Hsieh CF, Wu S, Lundström E, Rudberg AS, et al. Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery. Cochrane Database of Systematic Reviews 2019, Issue 11. Art. No: CD009286. [DOI: 10.1002/14651858.CD009286.pub3] - DOI - PMC - PubMed
Mead 2011
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Mead 2012
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