Editorial
Combination Therapy in Moderate to Severe Alzheimer’s Disease – Overview and Discussion Points for the Future
José L Molinuevo Consultant Neurologist, Alzheimer’s Disease and Other Cognitive Disorders Unit, Institut Clinic of Neuroscience, Neurology Service, Hospital Clinic, Barcelona
Summary
Two effective symptomatic therapies are available for Alzheimer’s disease: the cholinesterase inhibitors (ChEIs) and memantine, an N-methyl-D-aspartate receptor antagonist. Current data demonstrate that combination therapy with memantine and a ChEI produces symptomatic benefits in all domains of AD. The benefits of combination therapy are greater than those of ChEI monotherapy, are sustained long term and appear to increase with time.
Keywords Alzheimer’s disease, treatment, combination, memantine
Disclosure: José L Molinuevo has provided scientific advice or has been a data monitoring board member in return for consultancy fees from Pfizer, Eisai, MSD, Merz, Janssen-Cilag, Novartis, Lundbeck, Roche, Bayer, Bristol-Myers Squibb, GE Health Care, GlaxoSmithKline and Innogenetics. No funding was provided to the author for the preparation of this manuscript. Acknowledgement: Editorial support was provided by Cambridge Medical Communication Ltd and was funded by H. Lundbeck A/S. Received: 28 October 2011 Accepted: 21 November 2011 Citation: European Neurological Review, 2011;6(4):228–9 Correspondence: José L Molinuevo, Alzheimer’s Disease and Other Cognitive Disorders Unit, Institut Clinic of Neuroscience, Neurology Service, Hospital Clinic i Universitari, Villarroel 170, 08036, Barcelona, Spain. E:
JLMOLI@clinic.ub.es
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder which presents clinically as progressive cognitive impairment, loss of ability to carry out activities of daily living and the development of behavioural problems. Currently, research is focused on new medications to prevent or slow the advancement of the disease, and on techniques for earlier diagnosis. However, to date, medications aimed at disease modification have failed in clinical trials owing to lack of effect, or perhaps because they have not targeted a sufficiently early AD population.
While we await disease-modifying treatments, two symptomatic therapies are currently available: the cholinesterase inhibitors (ChEIs; donepezil, galantamine and rivastigmine) and memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist. Both categories of drug have demonstrated efficacy in AD when used as monotherapy.1–3
Despite the ChEIs and memantine having been available for some time, their use is still being optimised. At present, ChEIs are approved for the treatment of mild to moderate AD (and severe AD in some countries) and memantine is approved for the treatment of moderate to severe AD. Consequently, in the moderate stages of the disease, there is a period of overlap during which both drugs are indicated and could, therefore, be taken in combination. The aim of this short article is to summarise the current data on combination therapy with memantine and a ChEI in moderate to severe AD. More detailed reviews are available elsewhere.4,5
Efficacy Benefits, Across All Domains, Over and Above Monotherapy
The results of two six-month randomised controlled trials (RCTs) on the use of combination therapy in AD have been published. In the
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first study, patients with moderate to severe AD who were already receiving stable donepezil were allocated to receive concurrent memantine or placebo.6
Combination therapy produced significant
benefits over donepezil and placebo in all symptomatic domains: cognition (p<0.001; observed cases [OC]), function (p=0.02; OC), behaviour (p=0.01; OC) and global outcome (p=0.03; OC).6 results were seen for last observation carried forward analyses.6
Similar This
large study (404 patients randomised) provides the key evidence in support of combination therapy. Detailed post hoc analyses of this RCT have found significant benefits for combination therapy over donepezil and placebo in several cognitive, functional and behavioural subdomains, including memory, praxis, language, grooming, watching television, agitation/aggression and irritability/lability.7–9
In addition to
the benefits experienced by patients, caregivers reported significantly less distress owing to the patients’ agitation, night-time behaviour and appetite changes.7
mild to moderate AD.10
The second RCT was performed in patients with In this group of patients, combination therapy
with memantine and a ChEI did not show significant benefits over a ChEI and placebo, although there was a trend towards a benefit in cognition (p=0.186; OC).10
Memantine is licensed to treat moderate to severe AD (Mini Mental State Examination [MMSE] <20), so a meta-analysis was performed on the subgroup of patients with MMSE <20 from both of these combination therapy RCTs; only concurrent donepezil was permitted.11
Significant benefits were seen for memantine and donepezil combination therapy, in comparison with therapy with donepezil and placebo, in terms of cognition, function, behaviour and global outcome.11
© TOUCH BRIEFINGS 2011
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