Effects of Fluoxetine on Cognitive Functioning in Children with Down Syndrome: A Prospective Open-Label Exploratory Study of Safety and Efficacy

Background: Down syndrome (DS) is a major genetic cause of intellectual disability. In an animal model of DS, fluoxetine was shown to restore brain architecture and cognitive performance, acting primarily on the hippocampus, with effects persisting after treatment discontinuation. In this translational study, we assessed the safety and tolerability of fluoxetine at the standard labeled dose and explored selected efficacy endpoints to inform future clinical trials. Methods: The study was approved as a phase I, open-label study. Participants with full trisomy 21 received fluoxetine (10 mg/day) for 6 months, followed by a 6-month observation period. The primary endpoint, safety and tolerability, was evaluated through clinical examinations, biochemistry, plasma fluoxetine and norfluoxetine levels, electroencephalography, and electrocardiography at multiple time-points. As a secondary efficacy endpoint, we selected a set of cognitive tests to explore hippocampus-dependent functions and adaptive behavior. Results: Fourteen children with DS (8.1 ± 1.24 years; range 6-10) were enrolled, and 12 completed the 12-month study. No serious or severe adverse events (AEs) occurred. All AEs resolved without sequelae. Short-term terminal insomnia was observed in two patients. Neuropsychological assessments revealed improvements in visuospatial processing tasks during the study. Analysis of adaptive behavior suggested enhanced expression skills. Conclusions: These findings indicate that fluoxetine is safe in children with DS. The association with terminal insomnia warrants specific investigation in future trials and strategies to optimize tolerability are discussed. Efficacy analyses highlight the visuospatial processing domain as potentially responsive to treatment, supporting further research.