The antidepressant fluoxetine has no effect on brain recovery after acute stroke


The antidepressant fluoxetine has been suggested as a means to improve brain recovery after acute stroke.

However, a large randomized study on stroke patients at 35 Swedish hospitals shows that the drug has no such effect.

The study, which was led by researchers at Karolinska Institutet, is published in The Lancet Neurology.

Every year almost 14 million people around the world suffer a stroke, and half of those who survive end up with a permanent functional impairment. Research on animals and small studies on humans have shown that fluoxetine, an SSRI drug that inhibits the uptake of serotonin in the brain, can promote post-stroke brain recovery. studies have shown that the treatment causes new cells to be formed in the damaged area of the brain.

The effect on functional ability has now been interrogated in a large randomized study of acute stroke patients (the EFFECTS study). The researchers also studied adverse reactions to the drug and its effect on depression.

No recovery improvement

“Our study shows that fluoxetine does not improve recovery after stroke,” says Erik Lundström, stroke doctor and principal investigator of the EFFECTS study and researcher at the Department of Clinical Neuroscience.

“The number of depressions did indeed decrease, but the risk of bone fractures increased.”

The study included 1,500 patients from 35 Swedish hospitals between October 2014 and June 2019, making it the largest ever randomized controlled stroke study in Sweden.

The patients were randomly placed in either a group that received six months’ fluoxetine (20 mg) treatment or a placebo group, without the participants or the researchers knowing who was assigned to which.

Functional ability was then measured using the modified Rankin scale (mRS), which is the most common scale for rating the degree of post-stroke loss of function.

Three collaborative studies

EFFECTS collaborates with two other academic-driven studies of fluoxetine treatment after stroke (FOCUS and AFFINITY). The collated results from the 6,000 or so patients included in the three studies will be presented within the year.

“My advice is to refrain from using fluoxetine as a preventative treatment following stroke,” says Dr. Erik Lundström.

BUT …….

This prospective, observational, pilot cohort study had evaluated the association between SSRI therapy and outcomes related to disability and QOL in a real-world setting of patients with first-ever stroke undergoing rehabilitation in Singapore.

Among the 57 study participants, 38.6% were on SSRIs. SSRI therapy was used predominantly to aid in motor recovery. On average, SSRIs were prescribed for 31.4 ± 17.4 days and 80.6 ± 27.2% of the rehabilitation LOS.

Patients prescribed with SSRIs were younger and received more rehabilitation therapies compared with those not on SSRIs. Although SSRI therapy appeared to be beneficial in improving rehabilitation outcomes, differences between the SSRI and non-SSRI groups were no longer significant after adjustment for confounders.

Multiple linear regression results were consistent in subgroup analyses conducted among patients on fluoxetine in the SSRI group.

Since the publication of results from the FLAME trial [27], use of SSRIs in stroke rehabilitation has generated considerable interest. In the FLAME trial, 118 ischaemic stroke patients with motor deficit (Fugl-Meyer motor score, FMMS ≤ 55) were randomized to receive fluoxetine or placebo [27].

At the end of 90 days, the improvement in motor function from baseline was significantly higher in the fluoxetine group. Although results from the trial are promising, the current evidence for SSRI therapy to augment post-stroke recovery are still not compelling enough for stroke guidelines to recommend its routine use in clinical practice [28].

In our study, SSRI therapy was prescribed for about a third of study participants undergoing stroke rehabilitation. Among the majority of patients who received SSRIs (68.2%), the documented drug indication was for improvement of motor function.

A drug utilization study conducted in Switzerland had reported a similar proportion of stroke patients (26.9%) being prescribed SSRIs [30]. However, unlike our study, the use of SSRIs was mostly for treatment of depressive symptoms instead.

The uncertainty over the benefits of SSRI therapy in promoting stroke recovery could explain the observed difference in intended use of pharmacotherapy.

Our study has provided insights into the characteristics of stroke rehabilitation patients whom physicians may perceive as more likely to benefit from SSRI therapy. In addition to being younger, patients in the SSRI group may have a better premorbid condition (i.e. ADL-independent prior to stroke), with no atrial fibrillation, and with greater disability (lower baseline FIM-motor or MBI score) at admission for rehabilitation.

Previous studies have reported that although younger age and better premorbid function are predictive of more favourable post-stroke outcomes, severe disability at admission is associated with worse functional outcome at discharge from rehabilitation [50–53].

Based on results from the FLAME trial, which showed that fluoxetine is beneficial in patients with more severe motor impairment (FMMS ≤ 55) [27], physicians may have prescribed SSRIs with the intention of maximizing the likelihood of functional recovery during rehabilitation in patients with greater baseline disability.

For patients with atrial fibrillation, clinicians avoid prescribing SSRIs due to the possible risk of promoting QT prolongation and ventricular arrhythmia including torsade de pointes, which can be potentially life-threatening [54].

Previous research have indicated that SSRIs may have the potential to improve motor function, reduce disability (regardless of depression status) and enhance QOL post-stroke [31, 55].

These favourable effects could be attributed to the facilitation of motor output by the brain serotoninergic system [56] and modulation of inhibitory neural activity to promote motor learning [57]. However, findings from our study did not detect a significant association between SSRI therapy and stroke rehabilitation outcomes measured using FIM-motor, MBI and SAQOL-39g scores. Several reasons could be proposed to explain this discrepancy. Firstly, the use of SSRIs may only be useful in certain patient subgroups.

For example, in the FLAME trial, patients were excluded if they had haemorrhagic stroke, severe neurological impairment (National Institutes of Health Stroke Scale, NIHSS score > 20), substantial premorbid disability, severe aphasia or depression [27].

The average baseline stroke severity of patients included in most other trials that demonstrated a positive effect of SSRIs on disability was moderate based on a systematic review [31]. It had been suggested that the likelihood of detecting a clinical benefit would be greater if studies included patients with moderate baseline stroke severity and excluded those with very mild or very severe stroke [58].

In contrast, our study was an observational study in a regular inpatient rehabilitation setting and with minimal patient selection by study investigators. In addition, as the mean acute hospital LOS of the patients in our study was 14 days, many patients were likely not started on SSRIs within the first week of stroke, which may have diminished the effectiveness of the therapy [59].

Secondly, the use of disability and QOL scales in our study may not be sensitive enough to quantify improvement over the short period of stroke rehabilitation. In our study, patients were admitted for a mean duration of 32 days. In comparison, the FLAME trial followed patients for 90 days [27].

Although impairment scales related to neurological (e.g. NIHSS) or motor function (e.g. FMMS) may be most responsive to change [58], these scales were not routinely administered to patients at the two rehabilitation centres in our study.

Thirdly, there may be a time lag before the beneficial effects of SSRIs on improving disability or QOL become apparent. Results from an earlier meta-analysis showed that SSRI therapy should be sustained for at least 4 weeks to ameliorate disability after stroke [31].

Although the average duration of therapy in the SSRI group was 31 days, there were 8 (36.4%) patients who took SSRIs for < 4 weeks during rehabilitation. This would have made the detection of any treatment effect more difficult.

Lastly, even though most published trials have reported that SSRIs are useful to aid recovery after stroke, the possibility of publication bias cannot be totally excluded. Based on findings from a Cochrane systematic review, the funnel plot for trials investigating SSRI therapy for the outcome of disability appeared asymmetric on visual inspection [55], suggesting that the publication of studies may have been dependent on the nature of their results [60].

While it is possible that studies that reported positive results for SSRI therapy are more likely to be published, asymmetry in funnel plots could also be due to selective outcome reporting, poor methodological quality leading to spuriously inflated effects in smaller studies, true heterogeneity and even chance [60].

In addition to the FLAME trial, the results of ongoing multi-centre trials, namely AFFINITY (Assessment oF FluoxetINe In sTroke recoverY) and EFFECTS (Efficacy oF Fluoxetine—a randomisEd Controlled Trial in Stroke), should be able to more robustly inform the efficacy of fluoxetine for stroke recovery [3].

Based on our multiple linear regression analyses, the frequency of rehabilitation therapies (specifically number of physiotherapy and occupational therapy sessions per day) seem to be an important factor contributing to more favourable outcomes.

Physiotherapy and occupational therapy were provided to all patients during rehabilitation in our study. However, the frequency of these therapies may differ depending on the condition, motivation and family support of each patient.

Recovery after stroke is a complex process that occurs through a combination of spontaneous and learning-dependent processes [61]. These therapies provide task-specific and context-specific training in ADLs (e.g. walking, feeding, toileting, bathing) that facilitate motor learning and promote post-stroke independence [61].

Although there is no clear consensus for the optimal frequency of therapy, increased training is generally accepted to be beneficial for recovery during stroke rehabilitation [62–64].

Results from our study should be viewed in light of some limitations. Firstly, due to the observational nature of our study, our findings may have been affected by unmeasured confounding. Nonetheless, we had taken into consideration many known factors that could affect stroke recovery including premorbid condition, comorbidities, rehabilitation LOS, medication use and therapies received during rehabilitation.

Secondly, the number of included patients in our study was small. Even though we performed a sample size calculation and enrolled more than the minimum target number of patients, the study is still inadequately powered for the subgroup analyses. Furthermore, post-hoc sample size estimation using results from our study showed that the minimum sample size required is 206 (103 in each group).

Thirdly, as different disability scales (FIM-motor or MBI) were used in the two rehabilitation centres, not all study participants were administered the same instrument. However, we successfully converted between the scores using validated crosstalk tables [39]. Lastly, while there might be differences between self-reported and proxy-reported QOL [46, 65], our sensitivity analyses showed that results from separate multiple linear regression analyses obtained via self-report and proxy, respectively, were largely consistent.

This prospective observational pilot cohort study had evaluated the association between SSRI therapy and the rehabilitation outcomes of disability and QOL among multi-ethnic patients with first-ever stroke admitted to two rehabilitation centres in Singapore. Among the 57 enrolled patients, 38.6% were prescribed with SSRIs, mainly to aid motor recovery during rehabilitation.

After adjustment for confounders, no significant association between SSRI therapy and stroke rehabilitation outcomes was found. However, findings from our study showed that physiotherapy and occupational therapy during rehabilitation enhanced post-stroke recovery, hence increasing the frequency of such therapies (as tolerated) should be considered for all stroke patients.

Similar results were observed from our subgroup analyses (restricting to patients on fluoxetine in the SSRI group), which are in line with the FOCUS (Fluoxetine Or Control Under Supervision) pragmatic trial suggesting that fluoxetine does not improve post-stroke disability [66].

The results of other ongoing multi-centre trials, namely AFFINITY and EFFECTS, to investigate the effects of fluoxetine in patients with recent stroke, should provide more evidence on any benefits of pharmacotherapy for functional recovery and enhancement of health-related QOL after stroke.

Nonetheless, as a previously published meta-analysis had demonstrated an improvement in disability among Chinese patients who received SSRI therapy (but not among Caucasian patients) [31], while these multi-centre trials (FOCUS, AFFINITY and EFFECTS) are conducted in countries with predominantly Caucasian populations (i.e. United Kingdom, Australia, New Zealand and Sweden), future research should also be performed in Asian populations.


More information: Erik Lundström et al. Safety and efficacy of fluoxetine on functional recovery after acute stroke (EFFECTS): a randomized, double-blind, placebo-controlled trial, The Lancet Neurology (2020). DOI: 10.1016/S1474-4422(20)30219-2


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