Changing stroke rehab and research worldwide now.Time is Brain! trillions and trillions of neurons that DIE each day because there are NO effective hyperacute therapies besides tPA(only 12% effective). I have 523 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.

What this blog is for:

My blog is not to help survivors recover, it is to have the 10 million yearly stroke survivors light fires underneath their doctors, stroke hospitals and stroke researchers to get stroke solved. 100% recovery. The stroke medical world is completely failing at that goal, they don't even have it as a goal. Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It lays out what needs to be done to get stroke survivors closer to 100% recovery. It's quite disgusting that this information is not available from every stroke association and doctors group.

Friday, July 17, 2020

Stroke neurorehabilitation: what future (if any) for fluoxetine?(type of antidepressant known as an SSRI)

My confidence level is zero that any stroke hospital will be following this. But surprise me.

Stroke neurorehabilitation: what future (if any) for fluoxetine?(type of antidepressant known as an SSRI)



by Giuseppe Reale, MD – Department of Neurosciences, Università Cattolica del Sacro Cuore – Rome
Nine years ago, the FLAME trial burst in the stroke neurorehabilitation panorama1. This trial (n=118) showed that ischemic stroke patients with hemiparesis/hemiplegia who had started fluoxetine 20 mg die within 5-10 days had better 3-months functional outcomes, if compared to placebo. The primary endpoint was Fugl-Meyer Motor Scale (FMMS); among secondary endpoints, modified Rankin Scale (mRS) and NIHSS motor sub-scores were lower too in the fluoxetine group. Noticeably, the median baseline NIHSS of both groups was about 13 and all patients received physiotherapy.
Putting together the results of the FLAME trial and the previous works on fluoxetine efficacy in animal models2, three large randomized controlled trials were soon started: FOCUS, EFFECTS and AFFINITY.
However, the results of the FOUCS trial (n= 3127), published in 2019, quite dampened the enthusiasm3. This trial included patients with ischemic and hemorrhagic stroke and a persistent neurological deficit (87% and 29% had a motor deficit or aphasia, respectively, in both arms), median baseline NIHSS was 6. Fluoxetine 20 mg die was started within 2-15 days after stroke and continued for three months, while the primary outcome was 6-months mRS score. The trial did not show any benefit of fluoxetine on 6-months disability, while it documented a reduced risk of post-stroke depression and an increased risk of bone fracture.
FOCUS and FLAME trials had some differences, such as baseline severity (NIHSS 6 vs 13), population (ischemic vs ischemic + hemorrhagic stroke, hemiparesis/hemiplegia vs persistent neurological deficit), enrolment timing (5-10 days vs 2-15 days), follow-up (three-months vs six-months, mRS vs FMMS), ancillary rehabilitation (not defined additional physiotherapy vs standard physiotherapy), so great expectations were addressed towards EFFECTS and AFFINITY, who were supposed to be presented at ESO-WSO Conference 2020 in Vienna. However, because of the SARS-CoV-2 pandemic, both trials were presented respectively by Prof. Erik Lündstrome and Prof. Hankey J. Graeme during a Webinar on May 13th (link here).
The EFFECTS trial was conducted in Sweden and enrolled 1500 patients. Treatment, inclusion criteria and primary outcome were the same of the FOCUS trial. Median baseline NIHSS was 3. Fluoxetine had a neutral effect on six-months disability, while reduced the risk of post-stroke depression and increased the risk of hyponatremia and bone fractures.
The AFFINITY trial enrolled 1280 patients from Australia, New Zealand and Vietnam. Patients with recent diagnosis of stroke (2-15 days) were randomized to receive fluoxetine 20 mg die or placebo. The primary endpoint was the mRS score distribution at six months. Baseline median NIHSS was 6. Once again, fluoxetine did not show any efficacy in reducing six-months disability. However, fluoxetine had a slight effect on patients’ mood, but increased the risk of seizures and bone fractures.
As showed above, these trials differed from the FLAME regarding the enrolled population, as they included patients with both ischemic and hemorrhagic stroke and less severe symptoms. Patients with mild symptoms would have probably had a good outcome independently from the experimental drug. In this view, subgroup analyses per stroke etiology, symptom severity and time of enrollment might shed new light on this topic. Furthermore, the possible efficacy of fluoxetine on post-stroke depression is potentially interesting for future trials. As well, the risk of bone fractures and of seizures should be carefully taken in account.
To definitely answer to these questions, a pooled metanalysis of FOCUS, AFFINITY and EFFECTS is already planned. Until then, in the future of fluoxetine there is still a FLAME of hope.

References
  1. Chollet F, Tardy J, Albucher J-F, Thalamas C, Berard E, Lamy C, Bejot Y, Deltour S, Jaillard A, Niclot P, et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol. 2011;10:123–130.
  2. McCann SK, Irvine C, Mead GE, Sena ES, Currie GL, Egan KE, Macleod MR, Howells DW. Efficacy of antidepressants in animal models of ischemic stroke: a systematic review and meta-analysis. Stroke. 2014;45:3055–3063.
  3. Dennis M, Mead G, Forbes J, Graham C, Hackett M, Hankey GJ, House A, Lewis S, Lundström E, Sandercock P, et al. Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial. The Lancet. 2019;393:265–274.

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