Fluoxetine and recovery after stroke
Authors: H Bart van der Worp
Journal: The Lancet (2018)

In 2011, publication of the randomised placebo-controlled FLAME trial in The Lancet Neurology fuelled hope that new and effective treatment strategies for stroke could be developed through repositioning of approved and often inexpensive drugs. The FLAME trial was done in nine centres in France, in 118 patients with ischaemic stroke and unilateral weakness. Treatment with the selective serotonin-reuptake inhibitor (SSRI) fluoxetine, started between days 5 and 10 after symptom onset, improved motor recovery and increased the chances of functional independence after 3 months.1Chollet 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: 123-130Summary Full Text Full Text PDF PubMed Scopus (666) Google Scholar Previously, small randomised trials had also suggested benefit of fluoxetine or other SSRIs,2Mead GE Hsieh CF Lee R et al.Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery.Cochrane Database Syst Rev. 2012; 11 (CD009286.)PubMed Google Scholar and SSRIs were shown to improve neurobehavioural outcomes by 52% in a meta-analysis of animal studies modelling stroke.3McCann SK Irvine C Mead GE et al.Efficacy of antidepressants in animal models of ischemic stroke: a systematic review and meta-analysis.Stroke. 2014; 45: 3055-3063Crossref PubMed Scopus (51) Google Scholar The apparently successful translation of results from animal models to the FLAME trial was welcomed after many years of translational failure.4Van der Worp HB Howells DW Sena ES et al.Can animal models of disease reliably inform human studies?.PLoS Med. 2010; 7: e1000245Crossref PubMed Scopus (906) Google Scholar However, the 2012 Cochrane review of SSRIs for stroke recovery found heterogeneity between trials and methodological limitations in a substantial proportion of these studies, and therefore concluded that large, well designed trials were needed to assess whether SSRIs indeed improve functional outcomes in patients with stroke.2Mead GE Hsieh CF Lee R et al.Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery.Cochrane Database Syst Rev. 2012; 11 (CD009286.)PubMed Google Scholar Some of the authors of this Cochrane meta-analysis took up the gauntlet themselves and started the large trials requested.5Mead G Hackett ML Lundström 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; 16: 369Crossref PubMed Scopus (55) Google Scholar The first and largest of these, FOCUS, has now been published in The Lancet by Martin Dennis and colleagues,6FOCUS Trial CollaborationEffects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial.Lancet. 2018; (published online Dec 5.)http://dx.doi.org/10.1016/S0140-6736(18)32823-XGoogle Scholar on behalf of the FOCUS Trial Collaboration. FOCUS was a pragmatic, multicentre, double-blind, randomised, placebo-controlled trial that recruited 3127 adult patients (61% men, mean age 71 years) with ischaemic stroke or intracerebral haemorrhage across 103 hospitals in the UK, over a period of 4·5 years. Patients were randomly allocated fluoxetine 20 mg once daily or matching placebo, initiated between 2 days and 15 days after stroke onset and continued for 6 months. The primary outcome was the score on the modified Rankin Scale at 6 months. Unfortunately, the trial did not demonstrate any benefit on functional outcome of fluoxetine compared with placebo at 6 months (adjusted common odds ratio 0·951 [95% CI 0·839–1·079]; p=0·439). Fluoxetine reduced the occurrence of depression in the first 6 months after stroke (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033) but increased the risk of bone fracture (45 [2·88%] patients vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). These data do not therefore support the use of fluoxetine with the aim of promoting functional recovery after stroke. The difference between the results of FLAME and those of FOCUS could be explained by several factors, including differences in patient populations, background therapies, and the timings of outcome assessment. The FLAME trial only enrolled patients with ischaemic stroke, whereas FOCUS also enrolled patients with intracerebral haemorrhage. However, predefined subgroup analyses (presented in the appendix) suggest that, in FOCUS, fluoxetine was also not effective in patients with ischaemic stroke. In FLAME, patients were treated for 3 months rather than 6 months, and outcomes were assessed at the end of the treatment period. Unfortunately, no information is given about functional outcomes in FOCUS at 3 months, but the absence of benefit of fluoxetine at 6 months suggests that if there is any benefit at 3 months, this does not persist. Finally, all patients in FLAME received physiotherapy during the treatment period, based on the assumption that a combination of fluoxetine and physiotherapy would enhance motor recovery. FOCUS was done against the background of routinely available stroke rehabilitation in the UK, so whether all patients also received physiotherapy and whether the intensity of this treatment was similar to that in FLAME are unknown. Hopefully, results of the ongoing large randomised trials of fluoxetine in stroke, AFFINITY and EFFECTS, and the planned pooled analysis of the three trials will provide more insight into the effects of fluoxetine in specific patient populations and with specific background therapies. Although the results of the trial are disappointing, FOCUS should be considered a success because the investigators managed to recruit the target of more than 3000 patients within a period of 4·5 years, and because this trial provides a reliable answer to the question of whether fluoxetine reduces disability after stroke. The main factors contributing to the successful completion of the trial are likely to have been that FOCUS addressed a clinically relevant question, had a simple and safe treatment strategy with a long window for inclusion, was supported by the UK and Scottish Stroke Research Networks, and had a pragmatic trial design. One example of pragmatism in FOCUS was the use of central statistical monitoring by the trial team rather than onsite monitoring by a professional organisation. Monitoring is intended to improve the quality and safety of a trial and to ensure that the conduct of the trial is in compliance with regulatory requirements. However, onsite monitoring is labour-intensive, expensive, and, importantly, of unproven effectiveness in investigator-initiated trials.7Al-Shahi Salman R Beller E Kagan J et al.Increasing value and reducing waste in biomedical research regulation and management.Lancet. 2014; 383: 176-185Summary Full Text Full Text PDF PubMed Scopus (305) Google Scholar, 8Berge E Stapf C Al-Shahi Salman R et al.Methods to improve patient recruitment and retention in stroke trials.Int J Stroke. 2016; 11: 663-676Crossref PubMed Scopus (20) Google Scholar The requirement of onsite monitoring is probably disproportionate in trials testing treatments with a well established and favourable safety profile such as fluoxetine, and might even have the risk of impeding rather than promoting successful completion of such trials. In this respect, FOCUS serves as an example to clinical trialists and regulators. I am Co-Chief Investigator of two multicentre randomised trials in patients with acute stroke, both related to repositioning of drugs: PRECIOUS (ISRCTN82217627) and MR ASAP (ISRCTN99503308). Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trialFluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Full-Text PDF Open Access