Fluoxetine, in combination with physical rehabilitation, appears to boost motor recovery in patients who have had an acute ischemic stroke.
The mechanism of the benefit isn’t entirely clear and it should not be assumed that all selective serotonin-reuptake inhibitors would exert the same effect, Dr. Francois Chollet and his colleagues reported Jan. 10 in the Lancet Neurology.
"Selective serotonin-reuptake inhibitors are not a uniform category of drugs and further basic science and pharmacology studies will also be needed to increase understanding of their mechanisms of action," wrote Dr. Chollet of the Centre Hospitalier Universitaire de Toulouse (France) and his coauthors (Lancet Neurol. 2011 Jan. 10 [doi:10.1016/S1474-4422(10)70314-8]).
The FLAME trial randomized 118 patients with acute ischemic stroke to either placebo or 20 mg fluoxetine once daily for 3 months. All patients received standard-of-care physical rehabilitation treatment.
The primary end point was a change in the Fugl-Meyer Motor Scale (FMMS), a 100-point scale that rates post-stroke motor recovery, with 0 being flaccid hemiplegia and 100 being normal movement.
Secondary end points included the National Institutes of Health stroke scale (NIHSS), the modified Rankin scale (mRS) and the Montgomery Asberg depression rating scale (MADRS).
The patients’ average age was 66 years. Men and women were similarly represented. The most common comorbidities were hypertension, dyslipidemia, smoking, prior cardiac disease, and diabetes. Stroke location was in the carotid territory in more than 80% of patients. More than half of the group had severe post-stroke disability as measured by the mRS.
There was good study retention in the trial, with two drop-outs in the fluoxetine group and four in the placebo group.
By the end of 90 days, the mean total improvement in FMMS scores in the active group was significantly greater than in the placebo group (36 vs. 22). The difference remained significant after researchers controlled for treatment center, age, stroke history, and baseline FMMS score. Upper and lower limb scores made similar improvements.
When the investigators analyzed the results of 76 patients who did not get thrombolytic therapy after their stroke, the mean improvement in FMMS scores still was significantly higher in the active group (38 vs. 24).
At the end of follow-up, the total NIHSS score was not significantly different between the treatment groups, but the motor component was significantly better in the active group. The mRS improved in both treatment groups but, after adjustment, the between-group difference was not significant.
After 90 days, the mean change in MADRS scores was significantly lower in patients who received fluoxetine than in those who received placebo. The frequency of clinical depression also was significantly lower in the active group (7% vs. 29%). However, the authors pointed out, this probably was not caused by the drug’s antidepressant effects alone. "In a previous study, a single dose of fluoxetine improved hand motor function and increased activity in the motor cortex, compared with placebo in patients recovering from stroke, showing a specific motor effect, whereas a mood effect is unlikely after a single dose."
Adverse events included one death in each group; each was related to the stroke. Other adverse events found in each group were hyponatremia, gastrointestinal symptoms, liver enzyme abnormalities, and psychiatric disorders. There were two serious adverse events in the fluoxetine group (hyponatremia and partial seizure). No patient discontinued therapy because of an adverse event.
Exactly how the antidepressant may benefit stroke patients remains unclear, the authors noted. Studies indicate that animals with a brain injury experience better functional recovery when treated with drugs that affect neurotransmitters. There is even evidence that such drugs might induce structural and physiologic brain changes after the insult. "One hypothesis is that a primary function of the brain serotoninergic system is to facilitate motor output, which emphasizes that the drug intake would be more efficient when paired with [physical] training," the authors wrote.
The study was sponsored by the French Ministry of Health. None of the authors declared any financial conflict.