Brain Trauma Stroke
Table 1: Reported Prospective Randomised Placebo-controlled Clinical Trials of Selective Serotonin Re-uptake Inhibitors in Motor Recovery After Ischaemic Stroke
Study
Drug(s) Dose, Regimen n Trial Design Time of and Treatment Duration
and once a day for (three groups) maprotiline 90 days
Pariente, Fluoxetine 20 mg (single dose) 8 Cross-over et al.32
Zittel, Citalopram 40 mg (single dose) 8 Cross-over et al.29
for 30 days (two groups)
15–30 days Finger tapping and Functional MRI; dynamometer
Acler, Citalopram 10 mg once a day 20 Paraller groups NR et al.30
More than Motor dexterity with None 6 months nine-hole-peg test NIHSS score
Yes
hyperactivation of motor cortices
Yes
TMS: modulation Yes of cortical excitability
HSS = Hemispheric Stroke Scale; MRI = magnetic resonance imaging; NIHSS = National Institutes of Health Stroke Scale; NR = not reported. Results of all trials showed positive effect on motor performance. Results of a randomised placebo-controlled trial by Gerdelat-Mas et al.33 cortical excitability induced by transcranial magnetic stimulation (TMS) with a single and chronic doses of paroxetine.
Figure 1: Improvement of Motor Performance and Hyperactivation of Primary Motor Cortex (S1M1) After a Single Dose of 20 mg Fluoxetine in Eight Recovering Stroke Patients Compared with Placebo
AB n=5 n=6
110 130 150
70 90
100 120 140 160 180 200
12 3 Trials
A
40 60 80
12 Trials z = 50 mm S1M1
0 2 4 6 8
Source: Pariente et al., 2001.32 cognitive deficits in rats and to stimulate neurogenesis.6,7 From published
experimental studies, several main conclusions can be emphasised that have been used in developing SSRI fluoxetine clinical trials.
•
First, these studies provide convincing evidence that there is obviously a large interaction between certain drugs and the recovery process in animal models. Norepinephrine and its agonists and antagonists have probably been the most studied drugs but others with potentially fewer side effects, such as SSRIs, could be expected to be beneficial.
•
Second, it appears that the cellular mechanisms underlying these significant effects of drugs acting on the CNS is beginning to be better understood. Additional basic research is needed to further investigate such pharmacological actions in the setting of rewiring and cellular growth in the damaged brain.
•
Third, drugs can have varying effects according to the dosage and also the dose regimen. For example, animal studies have found
250 3
20–30 % finger tapping and dynamometer improvement
11.4 % improvement in nine-hole-peg test 38.8 % improvement in NIHSS scores
in healthy individuals also confirmed the modulation of Inclusion After Stroke
Dam, Fluoxetine Fluoxetine 20 mg 48 Parallel groups 1–6 months Graded neurological None et al.28
scale (HSS)
Clinical Outcome Other Outcome Patients in Main Result Criteria
Criteria
Rehabilitation Programme Yes
10.7 % improvement in HSS scores
that, with increasing dose, amphetamine brings increasing then decreasing benefit.
•
Fourth, the timing of drug administration may be crucial. A therapeutic time window probably exists.
• Last, the effects of many drugs are highly dependent on experimental details. For example, drug infusion paired with behavioural training does not have the same behavioural effect as the drug infusion without training.
Monoaminergic Drugs and Motor Recovery After Stroke
Changes in motor performance were evaluated with the Fugl–Meyer Motor Scale (FMMS). Subsequent studies failed to show a superiority of D-amphetamine compared with placebo, even though some of these studies used the same protocols as one of the early intervention studies. A recent review summarised that it is currently impossible to draw any definite conclusions about the potential role of D-amphetamine in motor rehabilitation. Methylphenidate produces an increase in dopamine signalling through multiple actions. A prospective, randomised, double-blind, placebo-controlled trial with 21 patients early after stroke indicated that the combination of methylphenidate with physiotherapy over a period of three weeks improved motor function (as measured by the FMMS and a modified version of the Functional Independence Measure) and decreased depression. A subsequent neuroimaging study by Tardy et al. confirmed these findings.9–13
Many monoaminergic drugs have been tested in small or middle-sized clinical trials in patients with stroke. Amphetamines were probably the most studied, including a total of 287 patients. Only the first two studies were able to demonstrate beneficial effects. Walker-Batson et al. administered 10 mg D-amphetamine every fourth day, coupled with physiotherapy.8
Levodopa gave conflicting results both in single-dose and in repeated-dose trials. A randomised study with stroke patients (n=53) six weeks after stroke onset demonstrated that 100 mg levodopa given once a day over a period of three weeks in combination with carbidopa was significantly better than placebo in reducing motor deficits as measured by the Rivermead Motor Assessment. The improvement persisted over the subsequent three weeks. However, the study results have not been replicated by others up to now and a recent study with subacute stroke patients who received 100 mg levodopa per day for two weeks did not find a stronger improvement of motor functions than in the group treated with placebo.14–18
EUROPEAN NEUROLOGICAL REVIEW
Motor performances (%)
Z value
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