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News from the AAN Annual Meeting: Fluoxetine Appears to Aid Stroke Recovery

Friedman, Roberta Phd

doi: 10.1097/01.NT.0000398695.63196.30
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Investigators reported that stroke patients who took the antidepressant fluoxetine showed more improvement in a test of sensorimotor function compared to those taking placebo.

HONOLULU—The antidepressant drug fluoxetine may help stroke patients regain function, according to a multicenter trial in France where the researchers saw improved motor skill in daily living tasks.

The French researchers reported findings of the FLAME (Fluoxetine for motor recovery after acute ischaemic stroke) study here in 118 patients with ischemic stroke at the AAN annual meeting. The study was originally published online first before appearing in the February print edition of the Lancet Neurology.

This larger trial confirms and extends hints from initial smaller studies that suggested the drug could help in recovery from stroke, said investigator and neurologist François Chollet, MD, PhD, of the University Hospital of Toulouse, France, who presented the findings. Dr. Chollet told Neurology Today that the drug likely works through a “complex effect” that may include neuroprotection, neurogenesis, anti-inflammatory action, hyperactivation of motor cortices, and motivational factors as well.

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The FLAME study investigators enrolled patients from nine sites over five years. Patients were excluded if they were clinically diagnosed with depression and were taking antidepressant drugs, monoamine oxidase inhibitors, neuroleptic drugs, or benzodiazepines during the month before inclusion. The drug was given at 20 mg to patients, randomized to active or placebo treatment, beginning five to 15 days after stroke onset. The patients took their pills for three months. All had physiotherapy.

When depression occurred during the three months of treatment, clinicians were instructed to continue to provide fluoxetine or placebo, to avoid use of any other antidepressants, and if necessary, to give open-label fluoxetine (20 mg daily) so that the patient received either 20 mg (placebo) or 40 mg per day (fluoxetine).

Primary outcome was change in scores on the Fugl-Meyer motor scale, which assesses motor functioning, balance, sensation and joint functioning in hemiplegic post-stroke patients, at day 0 and 90. Secondary outcomes included NIH Stroke Scale (NIHSS), Rankin, and MADRS (Montgomery-Åsberg Depression Rating Scale) scores at the same time points.

Patients who took fluoxetine showed more improvement in their Fugl-Meyer scores on this test compared to those taking placebo (p=0.003). The mean scores at baseline on the Fugl-Meyer test were less for the placebo group, 13.4 (+/−8) than for the group taking fluoxetine, 17.1 (+/−11.7).

For the secondary outcomes including NIHSS, Rankin, and MADRS scores measured at the same time points, only the motor subset of the NIHSS differed significantly between the groups, with greater improvement for the patients taking the active drug (p=0.016).

The frequency of depression was significantly higher in the placebo group (29 percent) than in the patients taking fluoxetine (7 percent; p=0.002).

The Rankin test showed that more patients on fluoxetine achieved functional independence (scores of 1 or 2) at 90 days, compared with those taking the placebo (15 compared to five patients, p=0.015).

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“It does not have an effect on depression, these patients were not depressed,” Dr. Chollet said, “but there is an effect on the mood of our patients that may influence motivation and attention. It makes sense — when you get better motivation, you participate better in rehabilitation.”

“Ours is a demonstration in a small series of patients, but we have to be cautious,” said Dr. Chollet. “We need other studies, but it is a non-vascular new target for treatment and the field is open now.”

A Feb. 14 report from investigators at the University of Iowa gave a longer follow-up and also found good effect with fluoxetine in stroke recovery, he said. The report was published online first on the website of theAmerican Journal of Geriatric Psychiatry.

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Commenting on the FLAME study for Neurology Today, Bruce H. Dobkin, MD, professor of neurology at the University of California-Los Angeles, said: “This was a nicely done trial to address the questions it tackled. It is an important step but another one or two more steps are necessary before fluoxetine or related drugs can be routinely recommended.”

Dr. Dobkin, director of the neurologic rehabilitation and research program at the Geffen/UCLA School of Medicine, said that a larger trial is now warranted to see if selective serotonin reuptake inhibitors can help the actual functional use of the affected upper extremity for reaching and grasping, and the leg for walking, in the home and in the community.

“We need to see if indeed this class of drugs can improve motor control and daily functioning in moderate to severe stroke. If so, these medications could complement additional strategies to enable real improvement,” he said.

While the patients they selected made progress, “that improvement may not have been to the point where you can do much with the affected limb. The magnitude of gain is statistically significant, and probably had some clinical impact, but may not have been nearly enough for the patients to walk well or to use the upper extremity in daily activities,” Dr. Dobkin said.

“The Fugl-Meyer test, which was the primary outcome measure, reveals only that you can move across one or more joints, for reaching or for eating, but you only have to move against gravity, and that is not necessarily adequate motor control and strength for walking, for example, at a speed and energy cost for home and community activities,” he noted. The modified Rankin test also does not provide information on the actual use of the affected arm or leg; it indicates if the person can carry our tasks of daily life, he said.

Studies in animal models suggest that the neurotransmitters influenced by selective serotonin reuptake inhibitors may have an effect at the synapse for learning during practice and may facilitate the activation of motor systems, as well as increase growth factors, Dr. Dobkin noted. “The most up front explanation is that you are reducing any depression that might interfere with learning and concentration, but there could be more direct effects on the sensorimotor network.”

It is very important that the investigators took on patients with moderate to severe motor impairments, who tend not to recover as well with rehabilitation compared to most studies that follow patients with less severe stroke, Dr. Dobkin said.

He commented on the relatively slow accrual rate of the FLAME trial at each of the nine sites, and suggested that a future, larger trial might want to use less selective entry criteria, and “perhaps stratify subjects based on the Fugl-Meyer score.”

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The scale measures sensorimotor function in the upper and lower extremities: including reflex activity, volitional movements, normal reflex activity, movements (flexion, extension), coordination/speed joint pain, sensation, and passive joint motion. Most categories are scored on a 0-2 scale, with 0 indicating none; 1, partial; 2, full.

For more detailed information about the test, see

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Chollet F, Tardy J, Loubinoux I, et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol 2011;10(2):123–130.
Mikami K, Jorge RE, Robinson RG, et al. Effect of antidepressants on the course of disability following stroke. A J Geriatr Psychiatry 2011; E-pub 2011 Feb. 24.
    ©2011 American Academy of Neurology