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Randomised, double blind, placebo controlled trial with 12 weeks follow up.
7 trial centres in Latvia.
167 care dependent inpatients with moderately severe to severe dementia defined by DSM-III-R criteria (49% Alzheimer's disease, 51% vascular dementia) and with severity assessed by the Global Deterioration Scale (stages 5–7) and the Mini-Mental State Examination (<10 points). Exclusion criteria included duration of dementia <12 months; central nervous system active drugs within the previous 14 days; severe, chronic, or terminal diseases; impaired thyroid function, lowered B12 blood concentration; abnormal blood chemistry; alcoholism or drug addiction; major depression; learning disability; epilepsy; and Parkinson's disease. 1 patient was excluded from the analysis.
82 patients were assigned to memantine (5 mg/d during the first week and 10 mg/d during the next 11 wks) and 84 to placebo.
Main outcome measures
Clinical Global Impression of Change (CGI-C) rated by the physician, and the Behavioural Rating Scale for Geriatric Patients (BGP), subscore “care dependence,” rated by the nursing staff.
At 12 weeks, more patients receiving memantine had a positive treatment response (defined as 3 categories of improvement on the CGI-C) than those receiving placebo (p<0.001) (table⇓). There was a 3.1 point improvement on the BGP subscore “care dependence” for those in the memantine group compared with a 1.1 point improvement for those in the placebo group (p=0.016). A coincidental response of 3 categories of improvement on the CGI-C and an improvement of ≥15% on the BCG subscore was observed in more patients receiving memantine than those receiving placebo (n=151) (table⇓).
Memantine led to functional improvement and reduced care dependence in patients with severe dementia.
The cholinergic hypothesis of memory loss has to contend with the glutamatergic hypothesis of amnesia and dementia.1 These studies by Imbimbo et al and Winblad and Poritis are based on these alternative approaches.
Acetylcholinesterase inhibitors (ACh-EIs) have been the most widely investigated drugs in mild to moderate AD. Measures of their efficacy should tap 4 areas: cognition, functional activity, non-cognitive behaviours, and independent ratings of global change. Compared with placebo, the AChEIs tacrine, donepezil, metrifonate, and rivastigmine show a modest improvement of cognitive function of 2–4 ADAS-Cog points over 6 months, with a return then to baseline values or less.2 Ratings of global impression of change improve 1/3–1/2 point. Non-cognitive dysfunction has rarely been studied, and improvements in activities of daily living (ADL) have been hard to detect, except for rivastigmine.3 Overall, up to one quarter of patients do well on AChEIs, but the majority see little to no benefit. Which quarter improves, we cannot predict. The decrease in burden of care has been studied less.
The study by Imbimbo et al is well designed and was done with a low dropout rate. Unfortunately, the magnitude of the cognitive benefit was in the lower half of the range reported for other AChEIs and the number with the change normally considered clinically significant (≥4 ADAS-Cog points) is not reported. But eptastigmine joins rivastigmine in showing substantial benefit on ADL. The dose response effect and the consistency of modest improvements in cognition and daily functioning support the clinical relevance of the results. Although the cholinergic tolerability of eptastigmine was favourable, 4.5% of patients developed a mild transient neutropenia, which was dose dependent and included 1 case of severe neutropenia in the eptastigmine 20 mg group (3 times daily). It is surprising that patients with neutropenia continued in the trial and that there is no comment on incident infections. Another patient on eptastigmine, 20 mg (3 times daily), however, developed aplastic anaemia, a risk of 0.3% (95% CI 0.01% to 1.7%), whereas the risk in the general population is 2 per million per year. The risk on eptastigmine, similar to that of clozapine, will probably limit the use of the drug, certainly if there is no blood monitoring and with safer alternative drugs available. Patient or carer convenience was also less with thrice daily medication compared with rivastigmine's twice and donepezil's once daily regimens.
Severe dementia imposes a great challenge to carers. Functional and global clinical endpoints are more relevant here than cognitive ones. Memantine is an N-methyl-D-aspartate antagonist, which blocks the exitotoxic effects of excess glutamate release, considered central to memory and behavioural dysfunction and to the pathology of AD and vascular dementia.1 The results of the memantine study by Winblad and Poritis appear to be unbiased. The coincidence of treatment effects in independent nursing and medical assessments supports the validity and clinical significance of the results, but the design allowed no examination for dose response effect. The reported benefits and tolerability need to be established in a much longer duration trial, with health economic analysis. Adverse effects (not described) and serious adverse effects (mainly cardiac deaths) were equivalent in the 2 groups. Memantine seems useful not only in severe AD but also in vascular and mixed dementias, and in those without substantive behavioural problems (neuroleptics, hypnotics, and some antidepressants were excluded in trial patients), found in approximately 40% of patients with AD. Although glutamate antagonists may induce transient psychoses, memantine is thought not to do so.
These 2 contrasting pharmacological approaches to AD, here studied at different levels of severity, leave key issues unanswered: who benefits? Is response genotype specific? How substainable and valuable is a 2 point drop in carer dependence (memantine) in progressive dementia? Are there longer term side effects? Are skills regainable without rehabilitation? And how do the modest gains translate into quality adjusted life years and reduce burden of care and costs? In the future, non-cognitive symptoms should be assessed because they increase disease progression and disability, predict high family burden and costs, and are the primary cause of institutionalisation.1 Memantine's possible advantage of neuroprotection suggests that treatment combinations with AChEIs might enhance the benefits of only 1 approach.
Source of funding: not stated.
For correspondence: Dr B Winblad, Karolinska Institutet, Department of Clinical Neuroscience and Family Medicine, Division of Geriatric Medicine, B 84, Huddinge University Hospital, 14186 Huddinge, Sweden. Fax +46 8 5858 5470.
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