Elsevier

The Lancet Neurology

Volume 10, Issue 2, February 2011, Pages 123-130
The Lancet Neurology

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Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial

https://doi.org/10.1016/S1474-4422(10)70314-8Get rights and content

Summary

Background

Hemiplegia and hemiparesis are the most common deficits caused by stroke. A few small clinical trials suggest that fluoxetine enhances motor recovery but its clinical efficacy is unknown. We therefore aimed to investigate whether fluoxetine would enhance motor recovery if given soon after an ischaemic stroke to patients who have motor deficits.

Methods

In this double-blind, placebo-controlled trial, patients from nine stroke centres in France who had ischaemic stroke and hemiplegia or hemiparesis, had Fugl-Meyer motor scale (FMMS) scores of 55 or less, and were aged between 18 years and 85 years were eligible for inclusion. Patients were randomly assigned, using a computer random-number generator, in a 1:1 ratio to fluoxetine (20 mg once per day, orally) or placebo for 3 months starting 5–10 days after the onset of stroke. All patients had physiotherapy. The primary outcome measure was the change on the FMMS between day 0 and day 90 after the start of the study drug. Participants, carers, and physicians assessing the outcome were masked to group assignment. Analysis was of all patients for whom data were available (full analysis set). This trial is registered with ClinicalTrials.gov, number NCT00657163.

Findings

118 patients were randomly assigned to fluoxetine (n=59) or placebo (n=59), and 113 were included in the analysis (57 in the fluoxetine group and 56 in the placebo group). Two patients died before day 90 and three withdrew from the study. FMMS improvement at day 90 was significantly greater in the fluoxetine group (adjusted mean 34·0 points [95% CI 29·7–38·4]) than in the placebo group (24·3 points [19·9–28·7]; p=0·003). The main adverse events in the fluoxetine and placebo groups were hyponatraemia (two [4%] vs two [4%]), transient digestive disorders including nausea, diarrhoea, and abdominal pain (14 [25%] vs six [11%]), hepatic enzyme disorders (five [9%] vs ten [18%]), psychiatric disorders (three [5%] vs four [7%]), insomnia (19 [33%] vs 20 [36%]), and partial seizure (one [<1%] vs 0).

Interpretation

In patients with ischaemic stroke and moderate to severe motor deficit, the early prescription of fluoxetine with physiotherapy enhanced motor recovery after 3 months. Modulation of spontaneous brain plasticity by drugs is a promising pathway for treatment of patients with ischaemic stroke and moderate to severe motor deficit.

Funding

Public French National Programme for Clinical Research.

Introduction

Thrombolysis with alteplase given within the first few hours of an ischaemic stroke has long been the only treatment recognised to improve the spontaneous recovery of neurological functions. However, we have learnt over the past decade, by use of neuroimaging and electrophysiological techniques, that spontaneous recovery of neurological functions is associated with a large intracerebral reorganisation of the damaged human brain.

Various interventions, such as monoaminergic drugs, have been shown to modulate brain plasticity after a stroke and to reduce the residual neurological deficit and subsequent disability.1, 2, 3 Amphetamines have enhanced recovery in animal models of acute brain lesions, whereas neuroleptic drugs or benzodiazepines have reduced it.1, 2, 3 Little evidence exists for the efficacy of serotonin-reuptake inhibitors in studies of animals, but these inhibitors have an acute neuroprotective action on the ischaemic brain and promote hippocampal neurogenesis.4, 5, 6 In clinical trials of amphetamine in patients with stroke, either no positive effect was noted on the recovery of motor function or the results were contradictory.7, 8, 9, 10, 11 The few small clinical trials of serotonin-reuptake inhibitors that have been reported (table 1) all suggest that drugs of this type might have a positive effect.13, 14, 15, 16 Use of functional MRI in other studies showed that single doses of fluoxetine and paroxetine overactivated motor cortices compared with placebo in both healthy individuals and patients with stroke, and use of transcranial magnetic stimulation showed that cortex overactivation was associated with drug-induced cortex hyperexcitability.12

In the fluoxetine in motor recovery of patients with acute ischaemic stroke (FLAME) trial, we aimed to test whether a 3-month treatment with fluoxetine would enhance motor recovery when given early after an ischaemic stroke to patients with moderate to severe motor deficits.

Section snippets

Participants

Patients who had an acute ischaemic stroke within the past 5–10 days that caused hemiparesis or hemiplegia were prospectively enrolled from nine stroke units in France. Those who were aged between 18 years and 85 years and who had Fugl-Meyer motor scale (FMMS) scores of 55 or less at baseline were eligible for inclusion.

Patients were excluded if they had severe post-stroke disability (National Institutes of Health stroke scale [NIHSS] score >20), substantial premorbid disability, or a

Results

Between March 14, 2005, and June 9, 2009, 118 patients were prospectively enrolled. The two groups were well balanced in terms of baseline and demographic characteristics and stroke severity (table 2). However, mean age was slightly higher and previous history of stroke was more frequent in the fluoxetine group than in the control group. FMMS score at inclusion was higher in the fluoxetine group than in the placebo group (table 2). NIHSS, mRS, and MADRS mean scores did not differ in the two

Discussion

We noted a positive effect on motor recovery in patients with acute ischaemic stroke who were treated with fluoxetine for 3 months. This effect, assessed as a change in FMMS score between day 0 and day 90, was noticeable in the FMMS subscores for both the upper and the lower limb at day 90. By contrast, no effect was noted with NIHSS at day 90. However, NIHSS motor component score at day 90 was lower in the fluoxetine group than in the placebo group, in agreement with the data for FMMS scores.

References (32)

  • WL Li et al.

    Chronic fluoxetine treatment improves ischemia-induced spatial cognitive deficits through increasing hippocampal neurogenesis after stroke

    J Neurosci Res

    (2009)
  • L Sonde et al.

    Effects of amphetamine and/or L-dopa and physiotherapy after stroke: a blinded randomized study

    Acta Neurol Scand

    (2007)
  • T Treig et al.

    No benefit from D-amphetamine when added to physiotherapy after stroke: a randomized, placebo-controlled study

    Clin Rehabil

    (2003)
  • T Platz et al.

    Amphetamine fails to facilitate motor performance and to enhance motor recovery among stroke patients with mild arm paresis: interim analysis and termination of a double blind, randomised, placebo-controlled trial

    Restor Neurol Neurosci

    (2005)
  • DJ Gladstone et al.

    Subacute Therapy with Amphetamine and Rehabilitation for Stroke Study Investigators. Physiotherapy coupled with dextroamphetamine for rehabilitation after hemiparetic stroke: a randomized, double-blind, placebo-controlled trial

    Stroke

    (2006)
  • D Walker Batson et al.

    Amphetamine paired with physical therapy accelerates motor recovery after stroke. Further evidence

    Stroke

    (1995)
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