Can an Antidepressant Improve Motor Recovery After Stroke? A Meta-Analysis of Adjuvant Fluoxetine Reveals Both New Hope and Safety Concerns

Abstract

Background: Stroke is a major cause of long-term disability, with motor impairments posing significant challenges to recovery. In 2011, fluoxetine, a selective serotonin reuptake inhibitor (SSRI), was reported to improve motor recovery in stroke patients by enhancing neuroplasticity and modulating the serotonergic system. However, its efficacy and safety in post-stroke rehabilitation remain controversial. The aim of the study was to evaluate the efficacy and safety of fluoxetine in improving motor recovery and health-related quality of life (HRQoL) after stroke.

Methods: This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search of PubMed, Scopus, and Google Scholar was performed for randomized controlled trials (RCTs) evaluating the effects of fluoxetine on motor recovery in post-stroke patients, up to March 2025. Data were analyzed using Review Manager 5.1.0. Motor recovery and HRQoL outcomes were reported as standardized mean differences (SMDs) using a random effects model, while adverse events were assessed as odds ratios (ORs) using a fixed effects model. The review was registered with PROSPERO (ID: CRD420251011077).

Results: Out of 1,173 identified studies, 23 RCTs comprising a total of 12,041 post-stroke patients met inclusion criteria. Fluoxetine significantly improved motor recovery (P = 0.01), particularly with a 90-day treatment duration (P = 0.006) at a daily dose of 20 mg (P = 0.05). HRQoL also improved significantly (P = 0.002). However, fluoxetine use was associated with a higher risk of adverse events (P < 0.00001), notably bone fractures (P < 0.00001), seizures (P = 0.009), and hyponatremia (P = 0.007).

Conclusions: Fluoxetine may offer benefits in enhancing motor recovery and HRQoL in post-stroke patients, especially when administered as a 90-day course at 20 mg/day. However, the increased risk of serious adverse events including bone fractures, seizures, and hyponatremia highlights the importance of careful patient selection and monitoring during treatment.