Abbas Kharal, MD, MPH
ESO-WSO 2020 Large Clinical Trials Webinar
EFFECTS Trial – Efficacy of Fluoxetine: A Randomized Controlled Trial in Stroke
May 13, 2020
Over the past decade, there has been much controversy regarding the potential benefit of selective serotonin reuptake inhibitors (SSRIs) in neuro-recovery and functional independence after stroke. After data from animal stroke studies showed that SSRIs may have potential neuroprotective properties,1 this concept was further analyzed in humans through a Cochrane review2 of 52 studies of a total of 4059 stroke patients, which suggested that SSRIs may improve disability after stroke; however, given the heterogeneity of data, solid conclusions could not be drawn. Furthermore, a randomized controlled clinical trial published in 2011 in Lancet on fluoxetine for motor recovery after acute ischemic stroke (FLAME trial) that enrolled 118 stroke patients showed improved motor recovery after stroke and functional independence (up to 17%) in those treated with fluoxetine versus placebo.3
Pooled evidence from these studies suggested that there was possibly some promising evidence to suggest that the use of SSRIs after acute stroke may lead to neurogenesis, improved motor recovery after stroke and functional independence; however, given the heterogeneity of the data, small sample sizes and methodological limitations, larger well-designed randomized controlled clinical trials were needed to better test this hypothesis in humans.2,4 This led to further development of three large randomized controlled clinical trials, namely FOCUS, EFFECTS ad AFFINITY, which planned to collectively enroll nearly 6000 patients.5,6
The effects of fluoxetine on functional outcomes after acute stroke (FOCUS) trial conducted in the UK published its results in December 2018 and showed no significant difference in functional outcomes in patients treated with fluoxetine versus placebo.7 Furthermore, higher rates of bone fractures and seizures were reported in the fluoxetine arm. Results from the other two trials namely, Efficacy of Fluoxetine – a randomized controlled trial in stroke (EFFECTS) out of Sweden and Assessment of Fluoxetine in Stroke Recovery – a randomized, double-blinded, placebo-controlled trial (AFFINITY) from Australia, New Zealand and Vietnam were presented May 13 at the European Stroke Organisation-World Stroke Organization 2020 Large Clinical Trials Webinar.
The EFFECTS trial tested whether 20mg of fluoxetine once daily, 6 months after an acute stroke improves functional outcomes, with modified Rankin scale score as the primary outcome. The trial enrolled a total of 1500 participants from 35 centers across Sweden, randomized 1:1 to fluoxetine versus placebo, all greater than 18 years of age, with ischemic and/or hemorrhagic stroke, randomized between 2 to 15 days after incident stroke. Those with prior history of epilepsy, depression, previous drug overdose, allergy or contraindication to fluoxetine or life-threatening illness with a life expectancy less than 12 months were excluded from the trial. Median age was 71 years, 62% male, 88% had ischemic stroke and median NIHSS was 3. Similar to results from the FOCUS trial, the EFFECTS trial showed no significant difference in functional outcomes at 6 months in patients treated with fluoxetine versus placebo. Those in the fluoxetine arm had a 2% higher risk of bone fractures although less rates of post-stroke depression compared to placebo.
Similar results were reported in the AFFINITY trial. In summary, pooled analysis of all three recent randomized controlled clinical trials that studied the effect of fluoxetine versus placebo after stroke showed no significant difference in functional outcomes between the two groups; however, those in the fluoxetine arm collectively suffered higher rates of new bone fractures and seizures, but a lower rate of depression. In conclusion, the authors do not recommend the common use of SSRIs for recovery after acute stroke.
1. Windle V, Corbett D. Fluoxetine and recovery of motor function after focal ischemia in rats. Brain Res 2005.
2. Mead GE, Hsieh CF, Lee R, et al. Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery. Cochrane Database Syst. Rev. 2012.
3. Chollet F, Tardy J, Albucher JF, et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): A randomised placebo-controlled trial. Lancet Neurol 2011.
4. Pinto CB, Saleh Velez FG, Lopes F, et al. SSRI and motor recovery in stroke: Reestablishment of inhibitory Neural Network Tonus. Front Neurosci 2017.
5. Mead 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.
6. Graham C, Lewis S, Forbes J, et al. The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: Statistical and health economic analysis plan for the trials and for the individual patient data meta-analysis. Trials 2017.
7. Dennis M, Mead G, Forbes J, et al. Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial. Lancet 2019.
So, a pooled analysis of the data from the three studies noted above failed to find a significant average effect. Okay, I get it. But here’s the thing: My brother suffered a stroke, so I do not really care about the average effect. I care about the potential effect that SSRI’s could have on an individual’s recovery. I would like to know more about the variance in outcomes. As an economist, I know that there is no such thing as a perfectly random sample–there is always some endogeneity. ALWAYS.
Were any other the patients in the treatment group significantly positively affected by the SSRI treatment regimen? Thank you so much for your dedication, and please know that your work matters.