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NIHR Signal A commonly-used antidepressant doesn’t improve recovery after stroke

Published on 12 February 2019

doi: 10.3310/signal-000729

The antidepressant fluoxetine works no better than placebo to reduce disability after a stroke, lowering hopes that had been raised by other smaller studies.

After a six month trial including more than 3,000 adult stroke patients recruited at 103 UK hospitals, researchers concluded that fluoxetine should not be used to promote recovery from stroke-related disability, or routinely prescribed to prevent depression after stroke.

Several smaller studies and animal trials had found promising results from the use of fluoxetine after stroke. However, this trial of fluoxetine 20mg daily for six months found no improvement in function among those taking the drug. Although people who took fluoxetine were less likely to get depression, they were more likely to have fractures. 

Other studies of fluoxetine after stroke are underway, but this trial does not support using it in standard post-stroke care.

Share your views on the research.

Why was this study needed?

There are around 100,000 strokes in the UK each year, and two-thirds of stroke survivors leave the hospital with a disability. Stroke is costly in terms of medical and social care, and in loss of earning potential.

The idea that a widely available inexpensive generic drug such as fluoxetine might improve function is very attractive. However, research until now has been small scale, and a Cochrane review called for larger-scale research to confirm or refute the theory.

This study was set up to find out whether patients diagnosed with stroke would have better functional outcomes when treated with fluoxetine for six months.

What did this study do?

Researchers recruited 3,127 adults with a clinical diagnosis of stroke, and no current depression or contradictions to fluoxetine, for the FOCUS double-blind randomised controlled trial. They were prescribed either fluoxetine 20mg (1,564) or identical placebo (1,563) for six months.

Functional status was measured after six months by postal questionnaire, followed up by telephone interview if the questionnaire was incomplete or not returned. The questionnaire used the modified Rankin Scale which categorises functionality from 0 (no symptoms) to 6 (dead), with scores of 3 and over indicating someone has moderate disability and is unable to live independently.

Researchers also looked at secondary outcomes including incidence of depression after six months and adverse effects.

This large, multi-centre trial was well-conducted, and the results are likely to be reliable.

What did it find?

  • There was no difference in the distribution of scores on the modified Rankin scale of function between participants who had taken fluoxetine and participants who had taken placebo (odds ratio 0.95, 95% confidence interval 0.84 to 1.08).
  • Adherence to medicine was similar in the two groups. Around two-thirds of people in each group took the study medicine for at least 150 days. Median duration of treatment was 185 days for the fluoxetine group and 183 days for the placebo group.
  • People who took fluoxetine were significantly (p=0.0033) less likely to be diagnosed with a new episode of depression by six months (13.4% compared to 17.2% on placebo) and significantly (p=0.0006) less likely to be prescribed a new antidepressant (17.9% compared to 22.8% on placebo).
  • People taking fluoxetine were significantly (p=0.0070) more likely to have bone fractures (2.88% compared to 1.47% on placebo).

What does current guidance say on this issue?

NICE has two guidelines on stroke; one on diagnosis and initial management (CG68, updated 2017) and another on stroke rehabilitation (CG162, published 2013). Neither recommends the routine use of antidepressants for stroke patients.

CG162 recommends that people should be monitored for signs of emotional difficulties, and people with stroke who develop anxiety and depression should be treated according to standard mental health protocols.

What are the implications?

The findings of the study have clear implications: fluoxetine should not be added to stroke care as a routine treatment on the basis of the current evidence available.

This study was designed to give a definitive and statistically reliable answer to whether fluoxetine improves recovery after stroke, and was well-conducted. The results are likely to be robust, and they support the current guidelines, which do not recommend routine use of fluoxetine.

Citation and Funding

FOCUS Trial Collaboration. Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial. Lancet. 2019;393(10168):256-74.

The study was funded by the UK Stroke Association and the NIHR Health Technology Assessment Programme project number 13/04/30.

Bibliography

NICE. Stroke rehabilitation in adults. CG162. London: National Institute for Health and Care Excellence. 2013.

NICE. Stroke and transient ischaemic attack in over 16s: diagnosis and initial management. CG68. London: National Institute for Health and Care Excellence. 2008 (updated March 2017).

Why was this study needed?

There are around 100,000 strokes in the UK each year, and two-thirds of stroke survivors leave the hospital with a disability. Stroke is costly in terms of medical and social care, and in loss of earning potential.

The idea that a widely available inexpensive generic drug such as fluoxetine might improve function is very attractive. However, research until now has been small scale, and a Cochrane review called for larger-scale research to confirm or refute the theory.

This study was set up to find out whether patients diagnosed with stroke would have better functional outcomes when treated with fluoxetine for six months.

What did this study do?

Researchers recruited 3,127 adults with a clinical diagnosis of stroke, and no current depression or contradictions to fluoxetine, for the FOCUS double-blind randomised controlled trial. They were prescribed either fluoxetine 20mg (1,564) or identical placebo (1,563) for six months.

Functional status was measured after six months by postal questionnaire, followed up by telephone interview if the questionnaire was incomplete or not returned. The questionnaire used the modified Rankin Scale which categorises functionality from 0 (no symptoms) to 6 (dead), with scores of 3 and over indicating someone has moderate disability and is unable to live independently.

Researchers also looked at secondary outcomes including incidence of depression after six months and adverse effects.

This large, multi-centre trial was well-conducted, and the results are likely to be reliable.

What did it find?

  • There was no difference in the distribution of scores on the modified Rankin scale of function between participants who had taken fluoxetine and participants who had taken placebo (odds ratio 0.95, 95% confidence interval 0.84 to 1.08).
  • Adherence to medicine was similar in the two groups. Around two-thirds of people in each group took the study medicine for at least 150 days. Median duration of treatment was 185 days for the fluoxetine group and 183 days for the placebo group.
  • People who took fluoxetine were significantly (p=0.0033) less likely to be diagnosed with a new episode of depression by six months (13.4% compared to 17.2% on placebo) and significantly (p=0.0006) less likely to be prescribed a new antidepressant (17.9% compared to 22.8% on placebo).
  • People taking fluoxetine were significantly (p=0.0070) more likely to have bone fractures (2.88% compared to 1.47% on placebo).

What does current guidance say on this issue?

NICE has two guidelines on stroke; one on diagnosis and initial management (CG68, updated 2017) and another on stroke rehabilitation (CG162, published 2013). Neither recommends the routine use of antidepressants for stroke patients.

CG162 recommends that people should be monitored for signs of emotional difficulties, and people with stroke who develop anxiety and depression should be treated according to standard mental health protocols.

What are the implications?

The findings of the study have clear implications: fluoxetine should not be added to stroke care as a routine treatment on the basis of the current evidence available.

This study was designed to give a definitive and statistically reliable answer to whether fluoxetine improves recovery after stroke, and was well-conducted. The results are likely to be robust, and they support the current guidelines, which do not recommend routine use of fluoxetine.

Citation and Funding

FOCUS Trial Collaboration. Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial. Lancet. 2019;393(10168):256-74.

The study was funded by the UK Stroke Association and the NIHR Health Technology Assessment Programme project number 13/04/30.

Bibliography

NICE. Stroke rehabilitation in adults. CG162. London: National Institute for Health and Care Excellence. 2013.

NICE. Stroke and transient ischaemic attack in over 16s: diagnosis and initial management. CG68. London: National Institute for Health and Care Excellence. 2008 (updated March 2017).

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Published on 5 December 2018

FOCUS Trial Collaboration

The Lancet , 2018

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 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. Funding UK Stroke Association and NIHR Health Technology Assessment Programme.

Expert commentary

So why did FOCUS show no benefit? Previous studies suggest that treatments targeting brain neurochemistry, like fluoxetine, requires the drug to be combined with training (i.e. physiotherapy) to enhance brain ‘plasticity’.

However, in FOCUS, all participants had access to standard UK clinical care, so might not have had enough intensive physiotherapy to improve recovery. It is also possible that the outcome measure used, the modified Rankin scale was not sensitive enough to pick up a specific beneficial effect on motor function.

The clear message for clinicians is that fluoxetine should not be given routinely in non-depressed stroke patients to improve recovery.

David J Werring, Professor of Clinical Neurology, UCL Institute of Neurology; Honorary Consultant Neurologist, National Hospital for Neurology and Neurosurgery

The commentator declares no conflicting interests

Expert commentary

Selective serotonin reuptake inhibitors promote neuroplasticity in experimental stroke models, and a clinical signal of benefit in improving motor recovery post-stroke was observed in the previous, smaller (n=118) FLAME trial. Unfortunately, no such benefit was seen in FOCUS, a larger (n=3,127), pragmatic, UK-based randomised controlled trial.

Compared to placebo, routine use of fluoxetine after a stroke did not improve functional outcome at six months. New rates of depression decreased by 3.8% (an effect lost at 12 months), offset by the 3% increased risk of bone fractures in the fluoxetine group.

Large, international trials (AFFINITY and EFFECTS) of similar design, in different healthcare and therapy systems, are still ongoing.

Dr Tim England, Clinical Associate Professor, University of Nottingham; Honorary Consultant Stroke Physician, Royal Derby Hospital

The commentator was not part of the study team who designed and coordinated the FOCUS trial but was the PI at one of the recruiting centres