Fluoxetine given soon after an ischemic stroke improves motor function in patients with severe motor deficits and increases the number of patients who are independent at 90 days, the results of a new trial show.
Lead author François Chollet, MD, from the Institut National de la Santé et de la Recherche Médicale at Hôpital Purpan in Toulouse, France, presented the results of a multicenter, randomized, double-blind, placebo-controlled trial called Fluoxetine in Motor Recovery of Patients with Acute Ischemic Stroke (FLAME) here at the 7th World Stroke Congress.
Dr. Chollet concluded that fluoxetine, “improves motor function of patients with severe motor deficit when given early after ischemic stroke…[and] increases the number of independent patients.”
Given that the drug is now generic — and therefore inexpensive, is easy to use and well-tolerated, and does not require any specialized facilities to use it, he suggested, these findings could have importance for public health worldwide.
SSRIs in Stroke
Selective serotonin reuptake inhibitors (SSRIs) modulate brain cortical activity, Dr. Chollet noted, and animal models have indicated pleiotropic beneficial effects of serotonin that may contribute to recovery from stroke.
However, there have been few clinical trials with SSRIs, and sample sizes have been very limited; however, the results have pointed to benefits. Therefore, FLAME was set up and carried out at several centers in France.
Patients with acute stroke causing hemiparesis or hemiplegia were eligible for the trial if they had no residual defect from a previous stroke, had a Fugl-Meyer Motor Scale (FMMS, 0 – 100-point scale) score of 55 or lower, could be randomly assigned between day 5 and 10 after the stroke, and had no significant deficits that could interfere with assessments (eg, deficits in comprehension or severe aphasia masking depression).
The participants also could not have clinically diagnosed depression or be taking antidepressants, monoamine oxidase inhibitors, neuroleptics, or benzodiazepines within the month before inclusion.
Patients with mild to severe motor deficits (N = 118) after ischemic stroke were randomly assigned equally to fluoxetine 20 mg orally daily or to placebo and followed-up for 90 days. Minimal drop outs occurred. All patients received physiotherapy as well as standard therapy by an organized in-patient stroke team. If depression occurred, patients could receive fluoxetine in an open-label fashion. Administration of another antidepressant drug stopped the study treatment. All patients were followed-up through day 90.
At baseline, the fluoxetine and placebo groups of the study were well matched for age, sex, body mass index, vascular risk factors, history of stroke, present stroke location (83% – 86% carotid territory), baseline stroke severity, administration of thrombolysis, and Montgomery-Åsberg Depression Rating Scale (MADRS) scores. The fluoxetine group had slightly less motor deficit at baseline (see table), which the investigators controlled for in their analysis.
The primary outcome measure was progression in the FMMS between baseline and day 90. Motor assessments were made at baseline and at days 30 and 90. Secondary endpoints were the National Institutes of Health Stroke Scale (NIHSS), the modified Rankin Scale (mRS), and the MADRS.
“The progression of the FMMS between inclusion and day 90 is superior in the fluoxetine group, and this is significant,” Dr. Chollet reported. “This is true for the group as a whole. This is…true for the upper extremity score and for the lower extremity score.” Greater improvements in motor recovery with fluoxetine were apparent as early as at day 15.
FMMS Scores at Day 90 vs Baseline, Mean (SD)
|Baseline stroke severity||(N = 59)||(N = 59)|
|FMMS||13.4 (8.8)||17.1 (11.7)|
|Upper extremity FMMS||4.7 (4.2)||5.5 (5.5)|
|Lower extremity FMMS||8.7 (6)||11.6 (7.9)|
|Day 90 scores||(N = 56)||(N = 57)|
|FMMS||35.1 (22)||53.7 (27.8)||< .001|
|Upper extremity FMMS||16.2 (16.6)||29.7 (22.2)||.001|
|Lower extremity FMMS||18.9 (8.2)||24 (7.9)||.001|
For the secondary endpoints, at day 90 there was no difference in NIHSS scores between the placebo and fluoxetine groups, but fluoxetine was associated with improvements in the motor NIHSS score (P = .011) and the mRS score. Among the placebo group, 8.9% of patients had a mRS score of 1 or 2 vs 26.3% in the fluoxetine group (P = .015). Scores of 1 or 2 indicate patient independence in carrying out most activities.
There was no difference in MADRS (depression) scores at 90 days, nor any difference in the scores’ variation from baseline (both P > .1).
The only adverse events that differed between the fluoxetine and placebo groups were depression (4 vs 17 events, respectively) and transient digestive disorders (14 vs 7, respectively).
For perspective, Dr. Chollet referred to earlier trials with other classes of drugs. He said the results with amphetamines were largely negative, and dopamine gave conflicting results. Small trials with serotonergic drugs had mostly positive results, suggesting a drug effect on motor recovery.
The mechanism of action of fluoxetine in this setting is not known, although several mechanisms are possible, including activation of primary motor cortices and possible attention-mediated mechanisms allowing better participation by patients.
Fluoxetine is a proven antidepressant, probably accounting for the lower prevalence of depression in that group. However, as the amphetamine trials were negative, one audience member suggested that fluoxetine was probably not working by increasing attention, or at least not solely.
Larger Trials Needed
Session moderator Bo Norrving, MD, professor of neurology at Lund University in Sweden, president of the World Stroke Organization, and congress cochairman, commented to Medscape Medical News, “I thought everybody was excited about this trial. It was the first of its kind of this magnitude, and it was showing a positive effect with a moderate effect size.”
He cautioned about interpreting a study with only about 120 patients. “It needs to be confirmed,” he said, and wondered whether the effect might disappear once the antidepressant effect goes away when fluoxetine is discontinued.
Even though the drug is fairly safe, inexpensive, and has a good history of use, Dr. Norrving said no one should try it outside of a clinical trial to treat motor deficits of stroke until confirmatory studies are completed.
The study was supported by the French National Program for Clinical Research. Dr. Norrving reported that he has received honoraria from Allergan, Bayer, and Boehringer and has done clinical trials work on endpoints committees with Servier, PhotoThera, and Syngis Pharma AG.
7th World Stroke Congress: Plenary III: Large Clinical Trials Closing Session. Presented Saturday, October 16, 2010.