Selective serotonin reuptake inhibitors to improve outcome in acute ischemic stroke: possible mechanisms and clinical evidence

Timo Siepmann, Ana Isabel Penzlin, Jessica Kepplinger, Ben Min-Woo Illigens, Kerstin Weidner, Heinz Reichmann, Kristian Barlinn, Timo Siepmann, Ana Isabel Penzlin, Jessica Kepplinger, Ben Min-Woo Illigens, Kerstin Weidner, Heinz Reichmann, Kristian Barlinn

Abstract

Background: Several clinical studies have indicated that selective serotonin reuptake inhibitors (SSRIs) administered in patients after acute ischemic stroke can improve clinical recovery independently of depression. Due to small sample sizes and heterogeneous study designs interpretability was limited in these studies. The mechanisms of action whereby SSRI might improve recovery from acute ischemic stroke are not fully elucidated.

Methods: We searched MEDLINE using the PubMed interface to identify evidence of SSRI mediated improvement of recovery from acute ischemic stroke and reviewed the literature on the potential underlying mechanisms of action.

Results: Among identified clinical studies, a well-designed randomized, double-blind, and placebo-controlled study (FLAME - fluoxetine for motor recovery after acute ischemic stroke) demonstrated improved recovery of motor function in stroke patients receiving fluoxetine. The positive effects of SSRIs on stroke recovery were further supported by a meta-analysis of 52 trials in a total of 4060 participants published by the Cochrane collaboration. Based on animal models, the mechanisms whereby SSRIs might ameliorate functional and structural ischemic-brain damage were suggested to include stimulation of neurogenesis with migration of newly generated cells toward ischemic-brain regions, anti-inflammatory neuroprotection, improved regulation of cerebral blood flow, and modulation of the adrenergic neurohormonal system. However, to date, it remains speculative if and to what degree these mechanisms convert into humans and randomized controlled trials in large populations of stroke patients comparing different SSRIs are still lacking.

Conclusion: In addition to the need of comprehensive-clinical evidence, further elucidation of the beneficial mechanisms whereby SSRIs may improve structural and functional recovery from ischemic-brain damage is needed to form a basis for translation into clinical practice.

Keywords: Acute ischemic stroke; SSRI; fluoxetine.

Figures

Figure 1
Figure 1
Possible mechanisms of action. The figure illustrates three possible mechanisms whereby SSRIs might improve structural‐brain tissue recovery from ischemia: stimulation of neurogenesis in the subependymal zone and hippocampal dentate gyrus, inhibition of microglia‐ and neutrophile‐induced inflammation mediated by cytotoxic inflammatory molecules, and improvement of cerebral vascular autoregulation (HO‐1, heme oxygenase‐1; VEGF, vascular endothelial growth factor).

References

    1. Acler, M. , Robol E., Fiaschi A., and Manganotti P.. 2009. A double blind placebo RCT to investigate the effects of serotonergic modulation on brain excitability and motor recovery in stroke patients. J. Neurol. 256:1152–1158.
    1. Barlinn, K. , Kepplinger J., Puetz V., Illigens B. M., Bodechtel U., and Siepmann T.. 2014. Exploring the risk‐factor association between depression and incident stroke: a systematic review and meta‐analysis. Neuropsychiatr. Dis. Treat. 11:1–14.
    1. Berkhemer, O. A. , Fransen P. S., Beumer D., van den Berg L. A., Lingsma H. F., Yoo A. J., et al. 2015. A randomized trial of intraarterial treatment for acute ischemic stroke. N. Eng. J. Med. 372:11–20.
    1. Budhdeo, S. , and Deluca G.. 2012. BDNF: a possible explanation of findings from the FLAME trial. Int. J. Stroke 7:E2.
    1. Chollet, F. , DiPiero V., Wise R. J. S., Brooks D. J., Dolan R. J., and Frackowiak R. S. J.. 1991. The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography. Ann. Neurol. 26:63–71.
    1. Chollet, F. , Tardy J., Albucher J. F., Thalamas C., Berard E., Lamy C., et al. 2011. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo‐controlled trial. Lancet Neurol. 10:123–130.
    1. Cramer, S. C. 2011. Listening to fluoxetine: a hot message from the FLAME trial of poststroke motor recovery. Int. J. Stroke 6:315–316.
    1. Cramer, S. C. , Nelles G., Benson R. R., Kaplan J. D., Parker R. A., Kwong K. K., et al. 1997. A functional MRI study of subjects recovered from hemiparetic stroke. Stroke 28:2518–2527.
    1. Dam, M. , Tonin P., De Boni A., Pizzolato G., Casson S., Ermani M., et al. 1996. Effects of fluoxetine and maprotiline on functional recovery inpoststroke hemiplegic patients undergoing rehabilitation therapy. Stroke 27:1211–1214.
    1. Dempsey, R. J. , Sailor K. A., Bowen K. K., Tureyen K., and Vemuganti R.. 2003. Stroke‐induced progenitor cell proliferation in adult spontaneously hypertensive rat brain: effect of exogenous IGF‐1 and GDNF. J. Neurochem. 87:586–597.
    1. Dirnagl, U. , Iadecola C., and Moskowitz M. A.. 1999. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 22:391–397.
    1. Go, A. S. , Mozaffarian D., Roger V. L., Benjamin E. J., Berry J. D., Blaha M. J., et al. 2014. Heart disease and stroke statistics–2014 update: a report from the American Heart Association. Circulation 129:e28–e292.
    1. Goyal, M. , Demchuk A. M., Menon B. K., Eesa M., Rempel J. L., Thornton J., et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N. Eng. J. Med. 2015. 372:1019–1030.
    1. Gu, W. , Brannstrom T., and Wester P.. 2000. Cortical neurogenesis in adult rats after reversible photothrombotic stroke. J. Cereb. Blood Flow Metab. 20:1166–1173.
    1. Hacke, W. , Kaste M., Bluhmki E., Brozman M., Dávalos A., Guidetti D., et al.; ECASS Investigators . Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N. Eng. J. Med. 2008. 359:1317–1329.
    1. Jiang, W. , Gu W., Brannstrom T., Rosqvist R., and Wester P.. 2001. Cortical neurogenesis in adult rats after transient middle cerebral artery occlusion. Stroke 32:1201–1207.
    1. Kirino, T. 2000. Delayed neuronal death. Neuropathology 20:95–97.
    1. Kraglund, K. L. , Mortensen J. K., Grove E. L., Johnsen S. P., and Andersen G.. 2015. TALOS: a multicenter, randomized, double‐blind, placebo‐controlled trial to test the effects of citalopram in patients with acute stroke. Int. J. Stroke 10:985–987.
    1. Lang, U. E. , Jockers‐Scherubl M. C., and Hellweg R.. 2004. State of the art of the neurotrophin hypothesis in psychiatric disorders: implications and limitations. J. Neural. Transm. 111:387–411.
    1. Lim, C. M. , Kim S. W., Park J. Y., Kim C., Yoon S. H., and Lee J. K.. 2009. Fluoxetine affords robust neuroprotection in the postischemic brain via its anti‐inflammatory effect. J. Neurosci. Res. 87:1037–1045.
    1. Liu, J. , Solway K., Messing R. O., and Sharp F. R.. 1998. Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J. Neurosci. 18:7768–7778.
    1. Lutz, W. , Sanderson W., and Scherbov S.. 2008. The coming acceleration of global population ageing. Nature 451:716–719.
    1. Majeed, F. , and Kamal A. K.. 2011. Can selective serotonin reuptake inhibitors (SSRI) improve motor recovery after stroke? What is the role of neuroplasticity? J. Pakist. Med. Associat. 61:1147–1148.
    1. Malberg, J. E. , Eisch A. J., Nestler E. J., and Duman R. S.. 2000. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 20:9104–9110.
    1. McCann, S. K. , Irvine C., Mead G. E., Sena E. S., Currie G. L., Egan K. E., et al. 2014. Efficacy of antidepressants in animal models of ischemic stroke: a systematic review and meta‐analysis. Stroke 45:3055–3063.
    1. Mead, G . Fluoxetine or Control under Supervision (FOCUS) trial: to establish the effect(s) of routine administration of Fluoxetine in patients with a recent stroke ISRCTN registry; ISRCTN83290762. doi: .
    1. Mead, G. E. , Hsieh C. F., Lee R., Kutlubaev M. A., Claxton A., Hankey G. J., et al. 2012. Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery. Cochrane Database Syst. Rev. 11:CD009286.
    1. Mead, G. E. , Dennis M., Lundstrom E., Murray V., Hackett M., and Hankey G. J.. 2013. Letter by Mead et al. regarding article, “Selective serotonin reuptake inhibitors for stroke: more trials are needed”. Stroke 44:e40–e41.
    1. Mikami, K. , Jorge R. E., Adams H. P. Jr, Davis P. H., Leira E. C., Jang M., et al. 2011. Effect of antidepressants on the course of disability following stroke. Am. J. Geriatr. Psychiatry 19:1007–1015.
    1. Mortensen, J. K. , and Andersen G.. 2015. Safety of selective serotonin reuptake inhibitor treatment in recovering stroke patients. Expert Opin. Drug Saf. 6:911–919.
    1. Mortensen, J. K. , Larsson H., Johnsen S. P., and Andersen G.. 2014. Impact of prestroke selective serotonin reuptake inhibitor treatment on stroke severity and mortality. Stroke 45:2121–2123.
    1. Mu, Y. , and Gage F. H.. 2011. Adult hippocampal neurogenesis and its role in Alzheimer's disease. Mol. Neurodegener. 6:85.
    1. Ozaki, H. , Yu A. Y., Della N., Ozaki K., Luna J. D., Yamada H., et al. 1999. Hypoxia inducible factor‐1alpha is increased in ischemic retina: temporal and spatial correlation with VEGF expression. Invest. Ophthalmol. Vis. Sci. 40:182–189.
    1. Palvimaki, E.‐P. , Laakso A., Kuoppamaki M., Syvilahti E., and Hietala J.. 1994. Up‐regulation of beta l‐adrenergic receptors in rat brain after chronic citalopram and fluoxetine treatments. Psychopharmacology 115:543–546.
    1. Pariente, J. , Loubinoux I., Carel C., Albucher J. F., Leger A., Manelfe C., et al. 2001. Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke. Ann. Neurol. 6:718–729.
    1. Santarelli, L. , Saxe M., Gross C., Surget A., Battaglia F., Dulawa S., et al. 2003. Requirement of hippocampal neurogenesis antidepressant treatments and animal models of depressive‐like behaviour. Behav. Pharmacol. 301:805–809.
    1. Schmidt, H. D. , and Duman R. S.. 2007. The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive‐like behaviour. Behav. Pharmacol. 18:391–418.
    1. Shin, T. K. , Kang M. S., Lee H. Y., Seo M. S., Kim S. G., Kim C. D., et al. 2009. Fluoxetine and sertraline attenuate postischemic brain injury in mice. Korean J. Physiol. Pharmacol. 13:257–263.
    1. Siepmann, T. , Kepplinger J., Zerna C., Schatz U., Penzlin A. I., Pallesen L., et al. 2015. The effects of pretreatment versus de novo treatment with selective serotonin reuptake inhibitors on short‐term outcome after acute ischemic stroke. J. Stroke Cerebrovasc. Dis. 24:1886–1892.
    1. Taupin, P. 2006. Adult neurogenesis and neuroplasticity. Restor. Neurol. Neurosci. 24:9–15.
    1. Tiradentes, R. V. , Pires J. G., Silva N. F., Ramage A. G., Santuzzi C. H., and Futuro Neto H. A.. 2014. Effects of acute administration of selective serotonin reuptake inhibitors on sympathetic nerve activity. Braz. J. Med. Biol. Res. 47:554–559.
    1. Wiltrout, C. , Lang B., Yan Y., Dempsey R. J., and Vemuganti R.. 2007. Repairing brain after stroke: a review on post‐ischaemic neurogenesis. Neurochem. Int. 50:1028–1041.
    1. Zittel, S. , Weiller C., and Liepert J.. 2008. Citalopram improves dexterity in chronic stroke patients. Neurorehabilit. Neural Rep. 22:311–314.

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