Safety and efficacy of fluoxetine on functional recovery after acute stroke (EFFECTS): a randomised, double-blind, placebo-controlled trial

Abstract

BACKGROUNDPrevious studies have suggested that fluoxetine could improve neurological recovery after stroke. The EFFECTS trial was designed to test the hypothesis that administration of fluoxetine for 6 months after acute stroke would improve functional outcome. METHODSEFFECTS was an investigator-led, parallel group, randomised, placebo-controlled trial that enrolled non-depressed stroke patients aged 18 years or older between two and 15 days after stroke onset in 35 hospitals in Sweden. The patients had a clinical diagnosis of ischemic or intracerebral haemorrhage with persisting focal neurological deficits at inclusion. A webbased randomisation system which incorporated a minimisation algorithm was used to allocate participants to fluoxetine 20 mg once daily or matching placebo capsules for 6 months with a ratio of 1:1. Patients, care providers, investigators, and outcomes assessors were masked to the allocation. The primary outcome was functional status, measured with the modified Rankin Scale (mRS) at 6 months. Patients were analysed according to their treatment allocation. EFFECTS is registered with ClinicalTrials.gov, number NCT02683213. FINDINGS Recruitment started 20 Oct 2014 and ended 28 June 2019, when the planned 1500 patients were included (750 to fluoxetine and 750 to placebo). mRS data were available for 737/750 (98%) in the fluoxetine group and 742/750 (99%) in the placebo group. The primary outcome -distribution across mRS categories-was neutral (common odds ratio adjusted for minimisation variables 0•94 [95% CI 0•78 to 1•13], p=0•42). Fluoxetine reduced depression

Fluoxetine for stroke recovery improvement – the doubleblind, randomised placebo-controlled FOCUS-Poland trial

“…In our study, one female receiving fluoxetine had a bone fracture, compared to no fractures in the placebo group. This is consistent with previous trials which also reported more frequent bone fractures in patients taking SSRIs [9][10][11]25] and confirms the findings from observational studies [26].…”

“…Two patients taking fluoxetine in our cohort required an additional dose of fluoxetine or a new antidepressant medication, compared to four in the placebo group. This is consistent with large trials evaluating the benefit of six months of fluoxetine administration, which have also reported that patients given fluoxetine were less likely than those given a placebo to have developed new depression at six months [9][10][11].…”

“…Our findings in a Polish cohort add to data from other trials based on the FOCUS protocol (FOCUS, AFFINITY and EFFECTS) [9][10][11] and confirm that daily administration of fluoxetine 20 mg for six months does not improve functional or general stroke outcome after six and 12 months.…”

“…To provide conclusive and robust evidence regarding the effect of SSRIs for stroke recovery, three large clinical trials with the same core protocol were initiated: FOCUS (Fluoxetine Or Control Under Supervision), AFFINITY (Assessment of Fluoxetine in Stroke Recovery) and EFFECTS (Efficacy of Fluoxetine -a Randomised Controlled Trial in Stroke) [9][10][11].…”

“…The trials recruited patients in different regions and countries, but used a common core protocol adapted to local settings. The results of the FOCUS trial were published in 2019 [9], and of the EFFECTS and AFFINITY trials in 2020 [10,11]. In all three large trials, fluoxetine treatment did not show a functional benefit in patients after stroke, but some safety concerns were raised, including an increased risk of epileptic seizures, falls, bone fractures and hyponatremia in the fluoxetine group versus the placebo group.…”