CNS Drugs

, Volume 32, Issue 10, pp 895–903 | Cite as

Potential Role of Selective Serotonin Reuptake Inhibitors in Improving Functional Outcome after Stroke

  • Janne Kaergaard MortensenEmail author
  • Grethe Andersen
Leading Article


The great advances in acute stroke treatment during the last decades have changed life after stroke considerably. However, the use of intravenous thrombolysis and endovascular thrombectomy is limited by a relatively narrow time window or contraindications for treatment. Further, patients receiving acute reperfusion therapies may still have cognitive and emotional complications due to underlying brain infarcts even though physical problems may almost disappear. Consequently, stroke is still a frequent cause of adult disability and death worldwide, and an effort to identify additional treatments to enhance recovery, preferably also feasible in the time after the acute phase, is warranted. Albeit several drugs and treatment modalities have been studied for their potential to enhance recovery after stroke, no treatment has unambiguously proven to potentiate the rehabilitation process. A promising candidate for pharmacological treatment is selective serotonin reuptake inhibitors (SSRIs), a group of commonly used antidepressants that may also possess neuro-regenerative properties. The current paper reviews the evidence for SSRIs as potential enhancers of stroke recovery and discusses the potential mechanisms behind the effects reported and the implications for the management of patients post-stoke, including potential adverse events and drug–drug interactions.


Compliance with Ethical Standards

Conflict of Interest

Janne Kaergaard Mortensen and Grethe Andersen have no conflicts of interest.


No funding was received to assist with the preparation of this review.


  1. 1.
    Hackett ML, Pickles K. Part I: frequency of depression after stroke: an updated systematic review and meta-analysis of observational studies. Int J Stroke. 2014;9(8):1017–25. Scholar
  2. 2.
    Mortensen JK, Johnsen SP, Andersen G. Prescription and predictors of post-stroke antidepressant treatment: a population-based study. Acta Neurol Scand. 2018. Scholar
  3. 3.
    Fuller RW, Wong DT. Serotonin reuptake blockers in vitro and in vivo. J Clin Psychopharmacol. 1987;7(6 Suppl):36S–43S.PubMedGoogle Scholar
  4. 4.
    Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med. 2009;60:355–66. Scholar
  5. 5.
    Wgner A, Montero D, Martensson B, Siwers B, Asberg M. Effects of fluoxetine treatment of platelet 3H-imipramine binding, 5-HT uptake and 5-HT content in major depressive disorder. J Affect Disord. 1990;20(2):101–13. Scholar
  6. 6.
    Cramer SC. Drugs to enhance motor recovery after stroke. Stroke. 2015;46(10):2998–3005. Scholar
  7. 7.
    Dam M, Tonin P, De Boni A, et al. Effects of fluoxetine and maprotiline on functional recovery in poststroke hemiplegic patients undergoing rehabilitation therapy. Stroke. 1996;27(7):1211–4.CrossRefGoogle Scholar
  8. 8.
    Acler M, Robol E, Fiaschi A, Manganotti P. A double blind placebo RCT to investigate the effects of serotonergic modulation on brain excitability and motor recovery in stroke patients. J Neurol. 2009;256(7):1152–8. Scholar
  9. 9.
    Chollet F, Tardy J, Albucher JF, et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol. 2011;10(2):123–30. Scholar
  10. 10.
    Savadi Oskouie D, Sharifipour E, Sadeghi Bazargani H, et al. Efficacy of citalopram on acute ischemic stroke outcome: a randomized clinical trial. Neurorehabil Neural Repair. 2017;31(7):638–47. Scholar
  11. 11.
    He YT, Tang BS, Cai ZL, Zeng SL, Jiang X, Guo Y. Effects of fluoxetine on neural functional prognosis after ischemic stroke: a randomized controlled study in china. J Stroke Cerebrovasc Dis. 2016;25(4):761–70. Scholar
  12. 12.
    Guo Y, He Y, Tang B, et al. Effect of using fluoxetine at different time windows on neurological functional prognosis after ischemic stroke. Restor Neurol Neurosci. 2016;34(2):177–87. Scholar
  13. 13.
    Pariente J, Loubinoux I, Carel C, et al. Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke. Ann Neurol. 2001;50(6):718–29.CrossRefGoogle Scholar
  14. 14.
    Zittel S, Weiller C, Liepert J. Citalopram improves dexterity in chronic stroke patients. Neurorehabil Neural Repair. 2008;22(3):311–4. Scholar
  15. 15.
    Gourab K, Schmit BD, Hornby TG. Increased lower limb spasticity but not strength or function following a single-dose serotonin reuptake inhibitor in chronic stroke. Arch Phys Med Rehabil. 2015;96(12):2112–9. Scholar
  16. 16.
    Berends HI, Nijlant J, van Putten M, Movig KL, IJzerman MJ. Single dose of fluoxetine increases muscle activation in chronic stroke patients. Clin Neuropharmacol. 2009;32(1):1–5.PubMedGoogle Scholar
  17. 17.
    Loubinoux I, Boulanouar K, Ranjeva JP, et al. Cerebral functional magnetic resonance imaging activation modulated by a single dose of the monoamine neurotransmission enhancers fluoxetine and fenozolone during hand sensorimotor tasks. J Cereb Blood Flow Metab. 1999;19(12):1365–75. Scholar
  18. 18.
    Loubinoux I, Pariente J, Boulanouar K, et al. A single dose of the serotonin neurotransmission agonist paroxetine enhances motor output: double-blind, placebo-controlled, fMRI study in healthy subjects. Neuroimage. 2002;15(1):26–36. Scholar
  19. 19.
    McDonnell MN, Zipser C, Darmani G, Ziemann U, Muller-Dahlhaus F. The effects of a single dose of fluoxetine on practice-dependent plasticity. Clin Neurophysiol. 2018;129(7):1349–56.CrossRefGoogle Scholar
  20. 20.
    Mead GE, Hsieh CF, Lee R, et al. Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery. Cochrane Database Syst Rev. 2012;11:CD009286. Scholar
  21. 21.
    Yeo SH, Lim ZI, Mao J, Yau WP. Effects of central nervous system drugs on recovery after stroke: a systematic review and meta-analysis of randomized controlled trials. Clin Drug Investig. 2017;37(10):901–28. Scholar
  22. 22.
    Gu SC, Wang CD. Early selective serotonin reuptake inhibitors for recovery after stroke: a meta-analysis and trial sequential analysis. J Stroke Cerebrovasc Dis. 2018;27(5):1178–89.CrossRefGoogle Scholar
  23. 23.
    Mead GE, Hsieh CF, Lee R, et al. Selective serotonin reuptake inhibitors for stroke recovery: a systematic review and meta-analysis. Stroke. 2013;44(3):844–50. Scholar
  24. 24.
    Jorge RE, Acion L, Moser D, Adams HP Jr, Robinson RG. Escitalopram and enhancement of cognitive recovery following stroke. Arch Gen Psychiatry. 2010;67(2):187–96. Scholar
  25. 25.
    Kim JS, Lee EJ, Chang DI, 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.CrossRefGoogle Scholar
  26. 26.
    Robinson RG, Adams HP. Selective serotonin-reuptake inhibitors and recovery after stroke. Lancet Neurol. 2011;10(2):110–1. Scholar
  27. 27.
    Gonzenbach RR, Taegtmeyer AB, Luft A, Russmann S. Fluoxetine and motor recovery after ischaemic stroke. Lancet Neurol. 2011;10(6):499–500. (author reply 500-1).CrossRefPubMedGoogle Scholar
  28. 28.
    Cramer SC. Listening to fluoxetine: a hot message from the FLAME trial of poststroke motor recovery. Int J Stroke. 2011;6(4):315–6. Scholar
  29. 29.
    Adams HP Jr, Robinson RG. Improving recovery after stroke: a role for antidepressant medications? Stroke. 2012;43(10):2829–32. Scholar
  30. 30.
    Marshall RS. Should every patient with stroke be on selective serotonin reuptake inhibitors? no. Stroke. 2012;43(11):3152–3. Scholar
  31. 31.
    Selim MH, Molina CA. Poststroke treatment with selective serotonin reuptake inhibitors: a journey from sadness to motor recovery. Stroke. 2012;43(11):3154–5. Scholar
  32. 32.
    Hackam DG, Mrkobrada M. Selective serotonin reuptake inhibitors and brain hemorrhage: a meta-analysis. Neurology. 2012;79(18):1862–5. Scholar
  33. 33.
    Shin D, Oh YH, Eom CS, Park SM. Use of selective serotonin reuptake inhibitors and risk of stroke: a systematic review and meta-analysis. J Neurol. 2014;261(4):686–95. Scholar
  34. 34.
    de Abajo FJ, Rodriguez LA, Montero D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. BMJ. 1999;319(7217):1106–9.CrossRefGoogle Scholar
  35. 35.
    Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med. 2003;163(1):59–64. Scholar
  36. 36.
    Dalton SO, Sorensen HT, Johansen C. SSRIs and upper gastrointestinal bleeding: what is known and how should it influence prescribing? CNS Drugs. 2006;20(2):143–51. Scholar
  37. 37.
    Mortensen JK, Larsson H, Johnsen SP, 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(2):420–6. Scholar
  38. 38.
    John S, Donnelly M, Uchino K. Catastrophic reversible cerebral vasoconstriction syndrome associated with serotonin syndrome. Headache. 2013;53(9):1482–7. Scholar
  39. 39.
    Singhal AB, Caviness VS, Begleiter AF, Mark EJ, Rordorf G, Koroshetz WJ. Cerebral vasoconstriction and stroke after use of serotonergic drugs. Neurology. 2002;58(1):130–3.CrossRefGoogle Scholar
  40. 40.
    Juang HT, Chen PC, Chien KL. Using antidepressants and the risk of stroke recurrence: report from a national representative cohort study. BMC Neurol. 2015;15:86. Scholar
  41. 41.
    Wang MT, Chu CL, Yeh CB, Chang LC, Malone DC, Liou JT. Antidepressant use and risk of recurrent stroke: a population-based nested case-control study. J Clin Psychiatry. 2015;76(7):e877–85. Scholar
  42. 42.
    Lippi G, Montagnana M, Favaloro EJ, Franchini M. Mental depression and cardiovascular disease: a multifaceted, bidirectional association. Semin Thromb Hemost. 2009;35(3):325–36. Scholar
  43. 43.
    He Y, Cai Z, Zeng S, et al. Effect of fluoxetine on three-year recurrence in acute ischemic stroke: a randomized controlled clinical study. Clin Neurol Neurosurg. 2018;168:1–6.CrossRefGoogle Scholar
  44. 44.
    Schellen C, Ferrari J, Lang W, Sykora M. VISTA Collaborators. Effects of SSRI exposure on hemorrhagic complications and outcome following thrombolysis in ischemic stroke. Int J Stroke. 2017. Scholar
  45. 45.
    Scheitz JF, Turc G, Kujala L, et al. Intracerebral hemorrhage and outcome after thrombolysis in stroke patients using selective serotonin-reuptake inhibitors. Stroke. 2017;48(12):3239–44. Scholar
  46. 46.
    Miedema I, Horvath KM, Uyttenboogaart M, et al. Effect of selective serotonin re-uptake inhibitors (SSRIs) on functional outcome in patients with acute ischemic stroke treated with tPA. J Neurol Sci. 2010;293(1–2):65–7. Scholar
  47. 47.
    Towfighi A, Ovbiagele B, El Husseini N, et al. Poststroke depression: a scientific statement for healthcare professionals from the american heart association/american stroke association. Stroke. 2017;48(2):e30–43. Scholar
  48. 48.
    Hackett ML, Anderson CS, House A, Xia J. Interventions for treating depression after stroke. Cochrane Database Syst Rev. 2008. Scholar
  49. 49.
    Hackett ML, Anderson CS, House A, Halteh C. Interventions for preventing depression after stroke. Cochrane Database Syst Rev. 2008. Scholar
  50. 50.
    Pinto CB, Saleh Velez FG, Lopes F, et al. SSRI and motor recovery in stroke: reestablishment of inhibitory neural network tonus. Front Neurosci. 2017;11:637. Scholar
  51. 51.
    Sale A, Hannan AJ, Maffei L, Guzzetta A. Noninvasive strategies to optimise brain plasticity: from basic research to clinical perspectives. Neural Plast. 2013;2013:863970. Scholar
  52. 52.
    Li WL, Cai HH, Wang B, et al. Chronic fluoxetine treatment improves ischemia-induced spatial cognitive deficits through increasing hippocampal neurogenesis after stroke. J Neurosci Res. 2009;87(1):112–22. Scholar
  53. 53.
    Ma L, Lu ZN, Hu P, Yao CJ. Neuroprotective effect of escitalopram oxalate in rats with chronic hypoperfusion. J Huazhong Univ Sci Technolog Med Sci. 2015;35(4):514–8. Scholar
  54. 54.
    Shimizu E, Hashimoto K, Okamura N, et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry. 2003;54(1):70–5.CrossRefGoogle Scholar
  55. 55.
    Fournier NM, Duman RS. Role of vascular endothelial growth factor in adult hippocampal neurogenesis: implications for the pathophysiology and treatment of depression. Behav Brain Res. 2012;227(2):440–9. Scholar
  56. 56.
    Lim CM, Kim SW, Park JY, Kim C, Yoon SH, Lee JK. Fluoxetine affords robust neuroprotection in the postischemic brain via its anti-inflammatory effect. J Neurosci Res. 2009;87(4):1037–45. Scholar
  57. 57.
    Shan H, Bian Y, Shu Z, et al. Fluoxetine protects against IL-1beta-induced neuronal apoptosis via downregulation of p53. Neuropharmacology. 2016;107:68–78.CrossRefGoogle Scholar
  58. 58.
    Kraglund KL, Mortensen JK, Grove EL, Johnsen SP, Andersen G. TALOS: a multicenter, randomized, double-blind, placebo-controlled trial to test the effects of citalopram in patients with acute stroke. Int J Stroke. 2015;10(6):985–7. Scholar
  59. 59.
    Mead G, Hackett ML, Lundstrom E, Murray V, Hankey GJ, Dennis M. The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: A study protocol for three multicentre randomised controlled trials. Trials. 2015. Scholar
  60. 60.
    Mortensen JK, Kraglund KL, Johnsen SP, Mors O, Andersen G, Buttenschon HN. The serotonin transporter gene polymorphisms and risk of ischemic stroke. Cerebrovasc Dis. 2018;45(3–4):187–92. Scholar
  61. 61.
    Kohen R, Cain KC, Mitchell PH, et al. Association of serotonin transporter gene polymorphisms with poststroke depression. Arch Gen Psychiatry. 2008;65(11):1296–302.CrossRefGoogle Scholar
  62. 62.
    Lee EJ, Oh MS, Kim JS, et al. Serotonin transporter gene polymorphisms may be associated with poststroke neurological recovery after escitalopram use. J Neurol Neurosurg Psychiatry. 2018;89(3):271–6. Scholar
  63. 63.
    Gelernter J, Cubells JF, Kidd JR, Pakstis AJ, Kidd KK. Population studies of polymorphisms of the serotonin transporter protein gene. Am J Med Genet. 1999;88(1):61–6.;2-K.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of NeurologyAarhus University HospitalAarhus CDenmark

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