The Role of Fluoxetine and SSRIs in Motor Recovery Following Acute Ischaemic Stroke


Very little is known about the mechanism of action of piracetam, but there is some evidence that it enhances glucose utilisation and cellular metabolism in the brain. A Cochrane Review concluded that “treatment with piracetam may be effective in the treatment of aphasia after stroke”.19


Other drugs, such as reboxetine, an inhibitor of the re-uptake of norepinephrine, moclobemide, an inhibitor of monoamine oxidase A, and donepezil, an inhibitor of acetylcholinesterase, have been tested in small series with variable results, which prevent any conclusion being drawn on their efficacy.2,3


Until now, there has been only limited evidence supporting or refuting the use of centrally acting drugs to enhance the effects of neurorehabilitation. Many reasons have been given to explain the difficulties encountered by the investigators: small number of patients, recruitment of patients (25–40 screened for one enrolled), heterogeneity in stroke types, sizes and locations of lesions, concomitant neurological symptoms (within-subject variability in recovery), standardisation of rehabilitation programmes, dose of the drug, specific chemical formulation of the drug under study (D- or DL-amphetamines), time of prescription, duration of treatment, etc. The interpretation is further complicated by conflicting results and the occurrence of side effects (noradrenergic drugs).


Selective Serotonin Re-uptake Inhibitors and Stroke Selective Serotonin Re-uptake Inhibitors, Stroke and Depression


Post-stroke depression (PSD) is a common disorder, affecting 30–50 % of hemiplegic patients within one year of their cerebral infarction. In the early stage, i.e. during the first three to four months after a stroke, PSD poses serious problems, such as worsened functional and vital prognoses as well as worsened quality of life of the patient and carer. In this context, however, SSRIs were first used as antidepressants and were tested in humans in PSD.


Selective Serotonin Re-uptake Inhibitors as a Treatment for Depressed Stroke Patients


Sixteen trials (17 interventions), with 1,655 participants, were included in a recent Cochrane review. Data were available for 13 pharmaceutical agents. There was some evidence of the benefit of pharmacotherapy in terms of a complete remission of depression and a reduction (improvement) in scores on depression rating scales, but there was also evidence of an associated increase in adverse events. From those series, two studies with the SSRI fluoxetine showed a benefit in depressed patients (Fruehwald et al. and Wiart et al.).20–24


Selective Serotonin Re-uptake Inhibitors Probably Also Prevent Post-stroke Depression


Fourteen trials involving 1,515 participants were included in a recent Cochrane review. Data were available for 10 pharmaceutical trials (12 comparisons) with different antidepressants. There was no clear global effect of pharmacological therapy on the prevention of depression. However, arguments exist for a positive effect of citalopram.25–27


Selective Serotonin Re-uptake Inhibitors and Motor Recovery After Stroke Small Trials


Few clinical trials with serotonin re-uptake inhibitors have been reported (see Table 1).28–31


EUROPEAN NEUROLOGICAL REVIEW They have all included small numbers of


Figure 2: Fluoxetine for Motor Recovery After Acute Ischaemic Stroke Trial Profile


118 patients randomly assigned


59 allocated to fluoxetine


59 allocated to placebo


1 died from respiratory distress after inhalation of food, 1 withdrew (severe hypoxia)


57 analysed for primary endpoint in full-analysis set at day 90


Source: Chollet et al., 2011.34


1 died from septic shock, 2 withdrew (1 kidney tumour, 1 pulmonary embolism)


56 analysed for primary endpoint in full-analysis set at day 90


Figure 3: Fluoxetine for Motor Recovery After Acute Ischaemic Stroke Trial – Adjusted Mean Fugl–Meyer Motor Scale Total Scores at Days 0, 30 and 90


60 50


10 20 30 40


0 0 30 60


Time from stroke (days) Placebo


Fluoxetine


Mean was adjusted for centre, age, history of stroke (at days 0, 30 and 90) and Fugl–Meyer motor scale (FMMS) score at inclusion (at days 30 and 90). Error bars represent 95 % confidence intervals. Source: Chollet et al., 2011.34


90


Acler et al. confirmed this finding in ten patients in the active-treatment group versus ten in the placebo group.30


Dexterity was significantly improved.


patients; all have results that suggest a positive effect on recovery after stroke. In an early trial, fluoxetine and maprotiline were tested against placebo for three months in patients with hemiplegic stroke enrolled one to six months after the stroke. The patients in the fluoxetine group (n=16) had a better outcome than those in the maprotiline or placebo groups.28


In


a double-blind, placebo-controlled cross-over trial, Zittel et al. investigated the effects of a single dose (40 mg) of citalopram in eight patients with chronic stroke.29


Proof of Concept


In a double-blind placebo-controlled study by our group, Pariente et al., by combining clinical motor testing and functional MRI motor assessment in patients recovering from post-stroke hemiplegia (n=8), showed that a single dose (20 mg) of fluoxetine improved hand motor function and was correlated with an overactivation of motor cortices on functional MRI (see Figure 1).32


In a subsequent double-blind,


placebo-controlled trial in healthy individuals, transcranial magnetic stimulation showed that the intake of a single dose of the serotonin re-uptake inhibitor paroxetine was associated with hyperexcitability of the primary motor cortex, whereas chronic intake was associated with hypoexcitability of the brain motor cortices. Serotonin re-uptake


251


Mean Fugl–Meyer motor scale total scores


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