Background/Aim: Stimulant medications can enhance mood and cognition in stroke rehabilitation, but human clinical trial results are inconclusive. We sought to prospectively study the effects of levodopa (LD) and/or methylphenidate (MPH) in combination with physiotherapy on mood and cognition following stroke in human subjects. Methods: Ischemic stroke patients were enrolled in our study 15 to 180 days after stroke onset. The patients were randomized into four medication groups (MPH, LD, MPH + LD, or placebo) and received a 15-day course of medication therapy (1 dose daily) and 45-min standard physiotherapy treatment daily. Mood and cognitive function were assessed at the study onset and 15, 90 and 180 days after study enrollment. Results: The strongest improvement of mood and cognition was found between baseline and the first follow-up immediately after the intervention. A significant improvement in mood was also found in the combined treatment group (MPH + LD) at 90 and 180 days, compared to the placebo group. Conclusions: A 15-day course of daily MPH + LD combined with physiotherapy over a 3-week period was safe and significantly improved mood status in ischemic stroke patients. Future studies are needed which determine the optimal therapeutic window for and dosage of psychostimulants as well as identify those stroke patients who might benefit the most from treatment.

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