Donepezil improved memory in multiple sclerosis in a randomized clinical trial
Krupp LB, Christodoulou C, Melville P, Scherl WF, MacAllister WS and Elkins LE;
Commented by , 16 Jun 2005
Background
Although cognitive dysfunction affects approximately 50% of patients with Multiple sclerosis (MS), only few clinical studies have evaluated efficacy of cognitive enhancing treatment. Acetylcholinesterase inhibitors compensate for the cortical cholinergic deficit in Alzheimers disease (AD), although the beneficial effect of these drugs is not considered to be specific for AD.
Donepezil is a new acetylcholinesterase inhibitor, which has shown possible effect (two open label trials) on cognitive dysfunction in MS and the aim of the current study was to evaluate efficacy in a double blind placebo-controlled trial.
Aim
To test if donepezil enhance verbal learning and memory as compared to placebo, and to test if other measures of cognitive function also enhances.
Methods
A total of 260 MS patients with mild verbal memory impairment (0.5 SD below normative data) on the Rey Auditory Verbal Learning Test, no severe cognitive or neurologic impairment (Mini Mental State Examination > or = 26; Expanded Disability Status Scale < or = 6.5) were screened and 81 patients were found eligible for the study.
A total of 69 patients were randomized to oral donepezil or placebo in a 24-week trial. Initial dose of donepezil was 5 mg per day increasing to 10 mg per day. The primary outcome was change in the Selective Reminding Test (SRT), and secondary outcome included self-reported impression of memory change and the physician global impression of cognitive change.
Results
There was a significant improvement in memory performance on the SRT in donepezil-treated patients compared to placebo (p= 0.043), which remained significant after controlling for age, EDSS, baseline SRT, sex and MS subtype.
There was no significant improvement on other cognitive tests, although self reported memory improvement was significantly higher in the donepezil group (p=0.006), and clinicians also reported improvement in donepezil treated individuals (p= 0.036).
There were no serious adverse events, although more subjects receiving donepezil (34.3%) compared with placebo (8.8%) reported unusual/abnormal dreams.
Conclusions
The study shows improved memory performance in MS patients with memory impairment but there was no significant effect onother cognitive domains. The study population was selected on the criteria of verbal memory impairment, and baseline SRT-scores were lower compared to other cognitive tests and therefore more likely to improve.
The study has a quite narrow focus on verbal learning and memory, which still is relevant since these domains are commonly affected in MS. An interesting comment regarding concomitant medication was brought up in a letter to the authors (ref. 1), since 14 subjects were taking anticholinergic bladder medication (oxybutyrnin and tolterone) that may have worsened their cognitive performance.
The authors reanalyzed their data without these patients and found insufficient statistical power, although the trend of treatment efficacy was still there. It is clear that there are methodological problems that need to be dealt with in future trials in this field.
Still, it is encouraging to see positive placebo-controlled data, which may open up for new trials and hopefully also new treatment options. There are several other interesting drugs that could be tested for cognitive benefits in MS, and especially glutamate receptor antagonists seem interesting in this regard.
References
1. Tsao JW, Heilman KM. Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology 2005; 64 (10); 1823; author reply 1823.