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. 2020 May;24(22):1–94. doi: 10.3310/hta24220

Fluoxetine to improve functional outcomes in patients after acute stroke: the FOCUS RCT.

Martin Dennis, John Forbes, Catriona Graham, Maree Hackett, Graeme J Hankey, Allan House, Stephanie Lewis, Erik Lundström, Peter Sandercock, Gillian Mead
PMCID: PMC7294394  PMID: 32452356

Abstract

BACKGROUND

Our Cochrane review of selective serotonin inhibitors for stroke recovery indicated that fluoxetine may improve functional recovery, but the trials were small and most were at high risk of bias.

OBJECTIVES

The Fluoxetine Or Control Under Supervision (FOCUS) trial tested the hypothesis that fluoxetine improves recovery after stroke.

DESIGN

The FOCUS trial was a pragmatic, multicentre, parallel-group, individually randomised, placebo-controlled trial.

SETTING

This trial took place in 103 UK hospitals.

PARTICIPANTS

Patients were eligible if they were aged ≥ 18 years, had a clinical stroke diagnosis, with focal neurological deficits, between 2 and 15 days after onset.

INTERVENTIONS

Patients were randomly allocated 20 mg of fluoxetine once per day or the matching placebo for 6 months via a web-based system using a minimisation algorithm.

MAIN OUTCOME MEASURES

The primary outcome was the modified Rankin Scale at 6 months. Patients, carers, health-care staff and the trial team were masked to treatment allocation. Outcome was assessed at 6 and 12 months after randomisation. Patients were analysed by their treatment allocation as specified in a published statistical analysis plan.

RESULTS

Between 10 September 2012 and 31 March 2017, we recruited 3127 patients, 1564 of whom were allocated fluoxetine and 1563 of whom were allocated placebo. The modified Rankin Scale score at 6 months was available for 1553 out of 1564 (99.3%) of those allocated fluoxetine and 1553 out of 1563 (99.4%) of those allocated placebo. The distribution across modified Rankin Scale categories at 6 months was similar in the two groups (common odds ratio adjusted for minimisation variables 0.951, 95% confidence interval 0.839 to 1.079; p = 0.439). Compared with placebo, patients who were allocated fluoxetine were less likely to develop a new episode of depression by 6 months [210 (13.0%) vs. 269 (16.9%), difference -3.78%, 95% confidence interval -1.26% to -6.30%; p = 0.003], but had more bone fractures [45 (2.9%) vs. 23 (1.5%), difference 1.41%, 95% confidence interval 0.38% to 2.43%; p = 0.007]. There were no statistically significant differences in any other recorded events at 6 or 12 months. Health economic analyses showed no differences between groups in health-related quality of life, hospital bed usage or health-care costs.

LIMITATIONS

Some non-adherence to trial medication, lack of face-to-face assessment of neurological status at follow-up and lack of formal psychiatric diagnosis during follow-up.

CONCLUSIONS

20 mg of fluoxetine daily for 6 months after acute stroke did not improve patients' functional outcome but decreased the occurrence of depression and increased the risk of fractures. These data inform decisions about using fluoxetine after stroke to improve functional outcome or to prevent or treat mood disorders. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) (Australasia/Vietnam) and Efficacy oF Fluoxetine - a randomisEd Controlled Trial in Stroke (EFFECTS) (Sweden) trials recruited an additional 2780 patients and will report their results in 2020. These three trials have an almost identical protocol, which was collaboratively developed. Our planned individual patient data meta-analysis will provide more precise estimates of the effects of fluoxetine after stroke and indicate whether or not effects vary depending on patients' characteristics and health-care setting.

TRIAL REGISTRATION

Current Controlled Trials ISRCTN83290762.

FUNDING

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 22. See the NIHR Journals Library website for further project information. The Stroke Association (reference TSA 2011101) funded the start-up phase.

Plain language summary

Fluoxetine, sometimes referred to by the drug company name Prozac, has been used for many years to treat people who are depressed, including after a stroke. However, studies have suggested that treatment with fluoxetine started soon after a stroke might improve patients’ physical recovery. The Fluoxetine Or Control Under Supervision (FOCUS) trial recruited 3127 volunteers who had had a stroke within the previous 2 weeks from 103 UK hospitals between 2012 and 2017. Participants were randomly allocated to take a 6-month course of fluoxetine or an identical placebo capsule containing no fluoxetine. They were followed up at 6 months and 12 months after recruitment. Patients completed questionnaires that indicated how much they had recovered, and also measured their mood, fatigue and quality of life. The results of the trial showed that the physical recovery of patients was very similar in both groups. This indicates that fluoxetine does not improve physical outcomes of stroke patients. However, participants receiving fluoxetine were less likely to develop depression after the stroke but once the fluoxetine was stopped these effects on mood disappeared. Unfortunately, patients on fluoxetine were slightly more likely to fall and fracture a bone than those on placebo. The FOCUS trial is the first of three large randomised controlled trials testing fluoxetine in stroke patients to be completed. The FOCUS trial results suggest that patients with stroke should not routinely be treated with fluoxetine. The other two trials will give us further information about the effects of fluoxetine after stroke and whether or not its effects differ between countries or ethnic groups.

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