This article summarizes the main past clinical trials with various pharmacologic agents used to enhance motor (see Table 1 ) and speech (see Table 2 ) recovery after stroke. Pharmacologic augmentation of conventional therapies to enhance stroke motor and speech recovery seems beneficial. However, most of the clinical trials have been small, with narrow eligibility criteria, and the results of some are ambiguous. Timing and dose of medication have been variable between studies, as has the type of PT/OT or ST performed. These issues need to be systematically explored in adequately powered, randomized, double-blind clinical trials. Although promising results have been reported, at this point, the use of these pharmacologic agents is not supported by class I evidence.
Discussed in this article:
- Central Nervous System Stimulators (Amphetamines and Methylphenidate)
- Dopaminergic Agonists
- Selective Serotonergic/Noradrenergic Reuptake Inhibitors
- Acetylcholinesterase Inhibitors (Galantamine/Donepezil/Memantine)
- Moclobemide: Monoamine Oxidase Inhibitor
Enderby and colleagues 32 investigated piracetam’s effects on speech and functional recovery in the subacute period (6–9 weeks after) of cerebral infarction in the carotid artery territory. Sixty-seven aphasic patients received piracetam (4.8 g/d) or placebo for 12 weeks together with standard inpatient rehabilitation and were assessed by BI and Kuriansky Test for ADLs and Aachen Aphasia Test (AAT) for the subset of patients with aphasia. AAT subtest scores revealed a significant overall improvement compared with baseline in favor of piracetam immediately after treatment. There was no significant difference in improvement of ADLs between the two groups.
Another large-scale, randomized, placebo-controlled clinical trial was performed by De Deyn and colleagues 33 3 years later in 927 patients with very acute ischemic stroke (<12 hours). These patients were recruited from 55 hospitals in 10 European countries, of whom 373 were aphasic and were analyzed separately from the others (placebo group, n = 193; treatment group, n = 180). The active group received piracetam 12 g in a bolus intravenously within 12 hours after stroke onset, followed by piracetam 12 g per day intravenously until the fourth day, then 12 g of piracetam per day orally until 4 weeks, and then 4.8 g per day for 8 weeks. The Frenchay Aphasia Screening Test (FAST) was used for aphasia and BI for ADLs. A statistically significant difference was found in favor of the treated aphasic group on the FAST test at day 84. In a predefined subgroup analysis of a group who were aphasic and treated within 7 hours of the stroke, there were statistically significant differences in language function on aphasia testing, and in other parameters of functioning at the end of the study period, in favor of the treated group.
Kessler and colleagues 35 performed a randomized (1:1) placebo-controlled clinical trial in 24 patients with acute ischemic stroke (14 days after) who received 6 weeks of 2400 mg of piracetam twice daily coupled with 30 sessions of ST 5 times a week for 60 minutes. The patients were assessed by AAT, PET, and neuropsychological battery that included a verbal fluency task, Corsi block span test, a modified laterally score after Oldfield, tests for apraxia, progressive matrices of Raven, and the Benton test. Both groups showed significant reduction in the token test error rate. Although the placebo group showed improvement in written language and in comprehension, the piracetam group showed significant improvement not only in the subtests for written language, naming on confrontation, and comprehension but also in spontaneous speech, especially in communicative verbal behavior, and in the semantic and syntactic structure of their speech. In the piracetam group, increase of activation effect was significantly higher in the left transverse temporal gyrus, left triangular part of inferior frontal gyrus, and left posterior superior temporal gyrus. However, the placebo group showed an increase of activation effect only in the left vocalization area.
A year later, another group from Germany confirmed Kessler and colleagues’ 35 findings with the same 6-week treatment protocol with the same outcome measures 35 but using electroencephalography (EEG) instead of PET. Both groups improved significantly in most of the assessments but improvement in the syntactic structure of spontaneous speech and reduction in the error rate were in favor of the piracetam group. In the piracetam group, EEG revealed a significant shift in the alpha rhythm from frontal to occipital regions, which can be interpreted as the improvement of the recovery. 36
Likewise, Gungor and colleagues 44 investigated the effects of piracetam on speech and general recovery in acute ischemic stroke but with a longer treatment protocol. Thirty patients received 4.8 g of piracetam daily or placebo (1:1 design); treatment of 6 months; and assessment by Gulhane Aphasia Test (GAT; includes spontaneous speech, reading fluency, auditory comprehension, reading comprehension, repetition, naming, and writing), mRS, BI, and NIHSS. Other than the auditory comprehension subtest of the GAT, no significant difference was noted in favor of piracetam treatment.
Piracetam was mainly used in speech recovery after stroke. Except for the work of Gungor and colleagues, 44 beneficial effects of earlier studies were not tested by more recent investigations. Another interesting finding is that, to our knowledge, there have been no studies performed with English-speaking subjects.
The first study investigating the effects of citicoline on motor recovery after stroke came from Hazama and colleagues 2 in 1980 in 165 participants with subacute/chronic (>3 months) stroke and who received a high dose of citicoline (1 g/d/8 weeks; n = 55), low-dose citicoline (250 mg/d/8 weeks; n = 56), or placebo (n = 54) coupled with a functional rehabilitation program. A 12-grade scale (Hemiplegia Function Test) showed that improvements by 1 or more grades in the fourth and eighth weeks were seen in 44.4% and 53.3% of the high-dose patients, in 29.3% and 54.8% of the low-dose treated patients, respectively. These rates of improvement were higher than the 29.3% and 31.8% rates in the placebo group. The difference reached statistical significance at week 8. More than a decade later, the same group performed another placebo-controlled clinical trial to confirm the results of the previous trial but with no low-dose group and limiting the chronicity of stroke by 1 year. The same 8-week design with high-dose and placebo groups going through the same Hemiplegia Function Test was performed with 248 patients. The rates of improvement by 1 or more grades in upper-extremity function were 67.8% in the citicoline group and 55.4% in the placebo group ( P = .047), with no safety concerns. After 2 trials, it was concluded that citicoline improves motor function in patients with poststroke hemiplegic under rehabilitation programs. 4
Iranmanesh and Vakilian 23 focused on the efficiency of citicoline to increase muscular strength in patients with nontraumatic very acute (<6 hours) hemorrhagic stroke. Thirty-two patients with supratentorial cerebral infarction received citicoline (250 mg intravenously twice a day) or placebo for 14 days, and their muscular strength was measured through physical examination before treatment and then 3 months later. The mean muscular strength in both groups before intervention was 2.5 out of 5 in manual muscle testing. Muscular strength in patients with cerebral hemorrhage receiving citicoline increased, and this suggests that citicoline may be effective in the treatment of patients with cerebral hemorrhage. 23
Citicoline, an agent used mainly for overall recovery after ischemic stroke, was also investigated for poststroke motor recovery. Although the positive results in Hazama and Ueda’s early large clinical trials were supported by another group with a smaller trial, 23 more studies are needed to reach an agreement on the beneficial effects of the agent.