Fluoxetine for Improving Functional Outcome After Stroke: A Systematic Review and Meta-Analysis of Randomised Controlled Trials

Abstract

Background: The 2012 Cochrane Review of Selective Serotonin Reuptake Inhibitors of randomised controlled trials (RCTs) in stroke demonstrated that fluoxetine might reduce disability even in patients who did not have to have mood disorders to be randomised. This hypothesis was tested in the FOCUS trial in 3127 patients with stroke, and so, to set the trial's results in context, we updated our searches to identify and include new RCTs of fluoxetine. Methods: Data sources included several databases, trials registers, reference lists of included studies, and contact with experts. Searches (from 2012) were performed in July 2018. We excluded RCTs which required patients to have mood disorder at randomisation. Co-primary outcomes were dependence and disability. Quality was appraised using Cochrane risk of bias methods. Dichotomous data were synthesised using risk ratios (RR) and continuous data using standardised mean differences (SMD). Sensitivity analyses explored the effect of study quality. Results: From the searches, 3412 references were identified, 426 duplicates removed, 2986 references screened, and 491 full texts assessed for eligibility. Six new completed RCTs (n=3710) were eligible making a total of 13 trials (n=4145). There was no difference in the proportion independent at end of treatment (3 trials, n=3249, 36·6% in fluoxetine vs 36·7% control; RR 1·00, 95% confidence interval 0·91 to 1.09, p=0·99, I2 78%) and no difference in disability (7 trials n=3404, SMD 0·05, -0·02 to 0·12 p=0·15, I2=81%). Fluoxetine was associated with better neurological scores, less depression but more seizures. When only the four (n=3283) high quality RCTs were included, the only statistically significant difference between groups was a small reduction in depression scores with fluoxetine. Conclusion: Fluoxetine does not reduce disability and dependency after stroke. It improves depression scores but probably increases seizures. Ongoing RCTs will determine whether its effects in stroke vary depending on ethnicity, background treatment and other factors. Funding Statement: Maree L. Hackett held a National Health and Medical Research Council Career Development Fellowship, Level 2 (APP1141328 2018-2021). This review was not funded. Declaration of Interests: Dr. Barugh has nothing to disclose. Dr. Soleimani has nothing to disclose. Dr. Rudberg has nothing to disclose. Dr. Lundstrom has nothing to disclose. Dr. Legg has nothing to disclose. Dr. Hankey reports grants from the National Health and Medical Research Council of Australia, outside the submitted work. Dr. Hackett reports grants from National Health and Medical Research Council, outside the submitted work. Dr. Hsieh has nothing to disclose. Dr. Mead reports grants from University of Edinburgh, during the conduct of the study. Dr. Kutlubaev has nothing to disclose. Dr. Dennis reports and I was co-chief investigator of the FOCUS trial which was included in the review, and received a grant from NIHR to run the trial. Dr. Tilney has nothing to disclose. Dr. Wu has nothing to disclose.