Fluoxetine Improves Motor Function in Stroke Patients

Pauline Anderson

January 10, 2011

January 10, 2011 — Patients who take the antidepressant fluoxetine after an ischemic stroke have more improved mobility and are more independent than those who take placebo, a new study has found.

The study results suggest that fluoxetine, a selective serotonin reuptake inhibitor (SSRI), could represent a new approach to treatment.

"We think that fluoxetine promotes an increase in the brain's capacity to reorganize; it acts on the rewiring of the brain," said the study's lead author, François Chollet, MD, professor of neurology at Toulouse University Hospital, France. "This opens another capacity, another target, another pathway, for the treatment of these patients."

Ischemic stroke patients are currently treated with thrombolytic tissue plasminogen activator, but down the road, perhaps fluoxetine or other SSRIs may also be a treatment option for these patients.

But before that can happen, several questions have to be answered, said Dr. Chollet. For example, researchers need to determine the optimal duration of treatment, the long-term effects of the treatment on stroke patients, and any possible additional effects on neuronal activity.

The trial, Fluoxetine in Motor Recovery of Patients with Acute Ischemic Stroke (FLAME) is published online January 10 in The Lancet Neurology. Results were first presented last fall at the 7th World Stroke Congress in Seoul, Korea, and reported by Medscape Medical News at that time.

More Independent

In this trial, the researchers enrolled 118 patients with ischemic stroke from 9 stroke units in France. Patients ranged in age from 18 to 85 years; had hemiplegia or hemiparesis, the most common deficits caused by stroke; and had Fugl-Meyer motor scale scores of 55 or less.

Scores on this scale range from 0 (flaccid hemiplegia) to 100 (normal movement), with 66 points for the upper limb and 34 points for the lower limb. Each item is rated as not performed, partly performed, or fully performed.

The participants, 59 patients in each group, were randomly assigned to fluoxetine, 20 mg daily, or placebo starting 5 to10 days after stroke onset and continuing for 3 months. All received physiotherapy from physiotherapists who were instructed to use the normal protocol for their center, as well as standard post-stroke care.

Physiotherapists made all motor assessments at day 0 (baseline) and then 30 days and 90 days after enrollment. Secondary endpoints included modified Rankin scale measured at baseline, day 30, and day 90.

The analysis at 3 months included 57 patients in the fluoxetine group and 56 patients in the placebo group. The researchers recorded significantly greater improvements in Fugl-Meyer motor scale score in patients taking fluoxetine (adjusted mean, 34.0 points; 95% confidence interval [CI], 29.7 - 38.4) than in those taking placebo (24.3 points; CI, 19.9 - 28.7; P = .003).

This gain was significant for both the upper and the lower limb scores.

The treatment group not only showed more improved mobility than the placebo group but also were more independent. At the end of the study, 34% of the treatment group scored 0, 1, or 2 on the Rankin scale compared with 11% of the placebo group.

Fluoxetine has many advantages — for example, it's relatively inexpensive because it no longer has a patent and it's widely available — but other SSRIs probably have similar positive effects, said Dr. Chollet. Another trial with paroxetine found that it, too, had beneficial post-stroke neurologic effects, he said.

Another paper published in 2010 showed that patients taking escitalopram had more marked improvement in cognition, particularly memory, compared with placebo recipients and that this finding was independent of the drug's effect on depression (Arch Gen Psychiatry. 2010;67:187-196).

Fluoxetine is also not a new drug, so its side effects are well known. In this trial, the drug was well tolerated, with only infrequent side effects that were generally mild.

Transient digestive disorders (nausea, diarrhea, and abdominal pain) were more common in the fluoxetine than in the placebo group (25% vs 11%). Other adverse events in the fluoxetine and placebo groups included hyponatremia (4% vs 4%) and hepatic enzyme disorders (9% vs 18%).

Depressive Symptoms

It’s not unusual for stroke patients to experience depressive symptoms after a stroke — especially if they have significant impairments — but this was less likely to be the case in the treatment group in this trial (5% vs 7%). "We observed more depression, and it was statistically significant, in the placebo group than in the fluoxetine group," said Dr. Chollet.

Although in this study fluoxetine was given to the patients as soon as possible after their stroke, there is no "window" of time during which it must be delivered, as is the case with tissue plasminogen activators (because of the hemorrhagic risk). But it appears that the earlier fluoxetine given, the better.

"What we know about the natural history of stroke is that patients recover mainly during the first 3 months; this is the time where you have the biggest improvement," said Dr. Chollet.

Although patients in this trial were treated for 3 months after their stroke, it's not yet clear what the optimal duration of treatment might be, he said. Other questions to be answered are the long-term effects of fluoxetine on stroke patients and whether the treatment has other benefits on neurologic function, for example, on vision or language, he added.

Encouraging Evidence

Research in rats, cited by the authors, suggests that fluoxetine has a neuroprotective effect in the postischemic brain through its anti-inflammatory effects and by increasing hippocampal neurogenesis.

These and other mechanisms, including increased activity of the motor cortex, may be at work in stroke patients taking fluoxetine, said Philip B. Gorelick, MD, director of the Center for Stroke Research, Department of Neurology and Rehabilitation, University of Illinois College of Medicine, Chicago, who was asked to comment on the study.

… fluoxetine could serve as both a mood and a motor recovery enhancer, which would be a welcome combination of benefits in these patients.

This trial provides "encouraging evidence for the use of fluoxetine in the treatment of recent ischemic stroke motor recovery," said Dr. Gorelick in an email to Medscape Medical News. "Since some 30%-50% of post-stroke patients are depressed, fluoxetine could serve as both a mood and a motor recovery enhancer, which would be a welcome combination of benefits in these patients."

Public Health Implications

In an editorial accompanying the study, Robert Robinson and Harold Adams from the University of Iowa, Iowa City, discussed the public health implications of administering an SSRI to stroke patients.

The potential savings are huge, considering that the American Heart Association estimates that the 2010 direct and indirect costs for stroke were $73.7 billion and that there are about 795,000 strokes a year in the United States, Dr. Robinson, the Paul Penningroth Chair of the Department of Psychiatry at the University of Iowa, told Medscape Medical News in an interview.

…. the amount of potential savings is just enormous.

"If you could improve the recovery of patients so that, say 10% or 20% of them were able to recover to a level where they didn't require assistance for everything they do, the amount of potential savings is just enormous."

However, Dr. Robinson cautioned that the study is small, so it's too early to recommend giving an SSRI to every ischemic stroke patient. "We need to do this kind of study with more than 1000 patients and really determine whether this is the way to go, because you're talking about a very fundamental change in the way patients with stroke are treated."

As for the question of how long the positive effects of an SSRI last in stroke patients, Dr. Robinson noted that a study he helped author, which is likely to be published later this year, shows that stroke patients who received fluoxetine for 3 months continue to improve for at least a year.

"We found that after you stop the medication at 3 months, the patients who received the active treatment continue to get better," he said. "They continue to improve at a significantly greater rate than the patients who receive placebo, even though they're not getting medication anymore."

The FLAME trial was funded by the Public French National Program for Clinical Research. The authors have disclosed no relevant financial relationships.

Lancet Neurol. Published online January 10, 2011.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.