(1)
Southhampton, United Kingdom
5.1 Introduction
Memantine is a noncompetitive, voltage-dependent N-methyl-D-aspartate (NMDA) receptor antagonist. It is licensed for the treatment of moderate to severe AD in the USA and EU, represented by patients with a Mini-Mental State Examination (MMSE) score of <20. Memantine can be used in treatment-naive patients, in patients withdrawn from acetylcholinesterase inhibitors (ChEIs), or as an add-on treatment in patients already stabilized on an ChEI, most commonly donepezil. It has a better tolerability profile than the ChEIs and seems to have particular advantages on the noncognitive symptoms related to agitation and language.
5.1.1 Glutamate and Memantine
Glutamate is an excitatory amino acid neurotransmitter found in cortical and hippocampal neurons. Evidence is accumulating to suggest that the sustained presence of synaptic glutamate due to poor reuptake by glial cells may lead to loss of calcium homeostasis within the neuron. During normal synaptic transmission, full depolarization of the membrane occurs when glutamate binds with the N-methyl-D-aspartate (NMDA) receptor after partial depolarization by other ionotropic glutamate receptors, e.g., alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate. This opens the cation channel which, at rest, is closed by a magnesium ion, allowing calcium ions into the neuron. The glutamatergic system in general, and NMDA receptors in particular, may play a significant role in the execution of synaptic dysfunction and neuronal death triggered by amyloid Aβ in AD. This suggests that NMDA receptor antagonists may influence these pathological processes. In fact, memantine, which is an uncompetitive NMDA receptor antagonist, with fast, voltage-dependent blocking properties, is able to selectively block pathological tonic NMDA receptor activation in the presence of soluble Aβ oligomers (Parsons et al. 2007; Albrecht et al. 2008) while preserving their physiological transient synaptic activation. Memantine, like magnesium, blocks the cation channel in the resting state; however, the binding of magnesium and memantine to the receptor is voltage dependent. It is postulated that during the chronic partial depolarization of the membrane, caused by the abnormal persistence of glutamate in the synapse and its effects on AMPA receptors, the voltage change causes magnesium to leave the channel, allowing calcium through. However, memantine, which requires a greater potential difference to dislodge it, remains in place blocking the channel until full depolarization from a physiological stimulus occurs. Thus, while blocking the abnormal leakage, it allows normal synaptic transmission. Chronic excessive calcium influx impairs neuronal homeostasis causing eventual neurodegeneration and may result in synaptic or dendritic damage, necrosis, or apoptosis resulting in cell death (Cacabelos et al. 1999; Lancelot and Beal 1998; Greenamyre and Young 1989). The excessive stimulation of the NMDA receptor, under conditions of energy deprivation such as ischemia and the resulting excitotoxicity, will impair long-term potentiation, a process necessary for memory and learning. Therefore, this hypothesized mode of action of memantine could provide both symptomatic improvements and long-term neuroprotective effects.
5.1.2 Effects of Memantine on Neurodegeneration
Preclinical studies have shown an extensive array of effects that demonstrate a neuroprotective effect for memantine in vitro and in animal models. In various studies memantine has been shown to protect neuronal cells against toxicity due to mitochondrial dysfunction and chronic neuroinflammatory effects on cholinergic neurons and to protect cholinergic neurons after NMDA-induced lesions. In animal models memantine can prevent neuronal damage, preserve acetylcholine terminals, and reduce Aβ-induced learning deficits. It can protect against Aβ-induced apoptosis and neurotoxicity in rat brains and reduce tau phosphorylation in AD-like models possibly by its effects on stimulating protein phosphatase 2a which is known to prevent tau phosphorylation. Whether any of these effects are relevant in patients is unknown, and its neuroprotective potential remains to be confirmed in clinical studies (Miguel-Hidalgo et al. 2002; Li et al. 2004).
However, several clinical trials have proven beneficial symptomatic effects of memantine in studies of AD (Reisberg et al. 2003; Tariot et al. 2004; Peskind et al. 2006), and meta-analysis of several trials suggests potential to reduce clinical worsening (Wilkinson and Andersen 2007; Weiner et al. 2011; Wilkinson 2012).
Interestingly in its early development, its mode of action and potential neuroprotective effect were seen as being relevant to the treatment of the ischemia related to vascular dementia (VaD), but early trials while showing some cognitive benefits were ultimately insufficiently positive to prompt further development for this indication.
5.2 Memantine in Vascular Dementia
Two studies have been published in VaD which had very similar designs. The MMM 300 study was a 28-week multicenter double-blind study conducted in France, which enrolled 321 patients with mild to moderate dementia (using DSM-III and MMSE 12–20) satisfying the criteria for probable VaD according to NINDS-AIREN criteria (Orgogozo et al. 2002). Patients with AD were excluded according to the protocol.
Overall the results were rather equivocal finding statistically significant improvements only on cognition using the Alzheimer’s Disease Assessment Scale cognitive portion (ADAS-cog) and MMSE although with some numerical advantage for memantine in all parameters. As has become familiar in subsequent VaD studies, the placebo group showed a lack of the deterioration normally seen in AD trials. Although there was a significant advantage for memantine in the cognitive subscale of the GBS, a composite measure of cognition and function, overall the GBS, the clinical global impression of change (CGIC) and nurses geriatric observation scale (NOSGER) all failed to show a significant advantage for memantine.
The authors argue that the demonstration of a cognitive advantage in a VaD population was a proof of concept and that the lack of decline in the placebo group may have meant that the study was underpowered leading to the equivocal results. This is something of a recurring theme in the memantine data set.
However, as a result of this argument, recruitment for the second study which was already underway was extended (MMM 500), perhaps giving the chance to test that assumption. In this study 548 patients were randomized to either 20 mg memantine daily or placebo in a 28-week multicenter study in the UK (Wilcock et al. 2002). The same entry criteria were used for probable VaD, but the mean MMSE at entry was slightly higher (range 10–22). The results were similar showing that, while there was some slight advantage for memantine in a number of sub-analyses, the only significant outcome was in cognition as determined by the ADAS-cog. The MMSE in the placebo population did not change over the 28 weeks, as predicted in this VaD population, but unfortunately neither did the MMSE in the memantine group.
Again subgroup analysis showed that there were greater benefits for memantine by grouping the patients with more severe dementia as defined by entry MMSE and with small vessel disease on imaging. This latter finding was confirmed in a combined analysis of the two studies when the baseline CT/MRI findings were separated into those with larger cortical infarctions, or large vessel disease, and those with white matter lesions and lacunes, or small vessel disease (Möbius and Stöffler 2002). Those with small vessel disease showed progressive decline in cognitive function compared with the large vessel group who showed no change after 28 weeks, and as a result, the symptomatic improvements were much greater in the small vessel group. This may suggest that while stoke and multiple infarctions are a risk factor for dementia, they represent brain damage rather than dementia, and the cognitive decline we see in VaD patient is caused by small vessel disease. It was then felt that there could be a rationale for treating more severe AD, and the most influential memantine study was undertaken in a group of moderately severe AD.
5.3 Memantine in AD
AD is defined by the pathological presence of amyloid plaques and neurofibrillary tangles in specific areas of the brain, but this is clearly only part of the story when it comes to the organ failure we see in patients with dementia. The processes which cause this failure are multiple, overlapping, and influence each another.
In AD dementia pathogenesis amyloid Aβ accumulation, excitotoxicity at NMDA receptors, formation of tau neurofibrils, disturbance of mitochondrial function, neuroinflammation, and small vessel disease all play a part.
Memantine has demonstrated neuroprotective qualities in a number of model systems, both in vivo and in vitro. Prevention of NMDA and glutamate-induced cell death has been shown in a number of culture systems, including rat retinal ganglion and cerebellar, cortical, mesencephalic, and hippocampal neurons. Interestingly, in other tissue culture experiments, memantine reduced tau hyperphosphorylation and promoted non-amyloidogenic APP processing. These effects may or may not translate to the patient with brain failure causing dementia and if so may explain some of the observed efficacy of memantine in patients with AD. Other studies have shown memantine has reduced cell loss in rat models of AD (Danysz and Parsons 2012), but it has not been shown to reduce brain atrophy in AD patients (Wilkinson et al. 2012).
5.3.1 Clinical Trials
Table 5.1
Overview of phase III trials of memantine in AD
Study | Duration/design | Study population | Efficacy scales included | |||
|---|---|---|---|---|---|---|
MMSE inclusion | n (ITT) | Cognition | Function | Global status | ||
MEM-MD-10 | 24-week, DB, PC | 10–19/10–22 | MEM 126/201 | ADAS-cog | ADCS-ADL23 | CIBIC-Plus |
Peskind (2006) | PBO 140/202 | |||||
LU-99679 | 24-week, DB, PC | 11–19/11–23 | MEM 166/318 | ADAS-cog | ADCS-ADL23 | CIBIC-Plus |
Bakchine and Loft (2008) | PBO 76/152 | |||||
MEM-MD-12 | 24-week, DB, PC, receiving ChEIsa | 10–19/10–22 | MEM 151/217 | ADAS-cog | ADCS-ADL23 | CIBIC-Plus |
Porsteinsson et al. (2008) | PBO 146/216 | |||||
MRZ-9605 | 28-week, DB, PC | 3–14/3–14 | MEM 126/126 | SIB | ADCS-ADL19 | CIBIC-Plus |
Reisberg et al. (2003) | PBO 126/126 | |||||
MEM-MD-01 | 24-week, DB, PC | 5–14/5–14 | MEM 171/178 | SIB | ADCS-ADL19 | CIBIC-Plus |
van Dyck et al. (2007) | PBO 165/172 | |||||
MEM-MD-02 | 24-week, DB, PC, receiving donepezil | 10–14/5–14 | MEM 104/202 | SIB | ADCS-ADL19 | CIBIC-Plus |
Tariot et al. (2004) | PBO 124/201 | |||||
IE-2101 | 24-week, DB, PC | 5–14/5–14 | MEM 100/207 | SIB-J | ADCS-ADL19-J | CIBIC-Plus-J |
Homma et al. (2007) | PBO 107/107 | |||||
LU-10116 | 16-week, DB, PC | 5–18/5–18 | MEM 124/128 | SIB | ADCS-ADL19 | – |
Chen et al. (2007) | PBO 125/130 | |||||
MEM-MD-22 | 24-week, DB, PC | 5–18/5–18 | MEM 132/132 | BGP-Cog | BGP-Dep | CIBIC-Plus |
Forest (2006) | PBO 131/131 | |||||
5.3.2 Moderately Severe AD
Nine randomized controlled trials of memantine in AD have been completed to date, 7 of which have been of 6 months duration (Table 5.1). The first controlled trial to report positive findings in AD was a study of mixed dementia and unlike the others was of 12 weeks duration, undertaken in a severe nursing home population (mean baseline MMSE 6.3) and only tested 10 mg daily rather than the currently licensed dose of 10 mg twice daily used in the others (Winblad and Poritis 1999). This study undertaken in Latvian nursing homes included 166 patients of whom 51 % had AD and 49 % VaD. The primary outcome measures were the CGIC as rated by a physician and the behavioral rating scale for geriatric patients (BGP) subscore “care dependence” as rated by a nurse. The overall outcomes of the study demonstrated a statistically significant advantage for memantine over placebo for both primary outcomes with 73 % of the memantine-treated patients improving on CGIC compared with only 43 % of the placebo group. After a responder analysis, the functional improvements were judged to be clinically relevant. A separate analysis of the AD patients which in fact only amounted to about 20 patients in each group showed an advantage for memantine which was used to support the licensing applications for moderate to severe AD along with the data published by Reisberg (Reisberg et al. 2003). This study was a 28-week double-blind placebo-controlled trial of 252 moderately severe outpatients (mean baseline MMSE 7.9) undertaken in the USA. The main outcome measures were the severe impairment battery (SIB), a cognitive scale validated to demonstrate change in severe AD patients, the Clinicians Interview-Based Impression of Change plus caregiver information (CIBIC-plus), the 19-item Alzheimer’s Disease Cooperative Study severe activities of daily living scale (ADCS-ADL), and the functional assessment staging tool (FAST). Other measures, including the MMSE, neuropsychiatric inventory (NPI), and a resource utilization scale, were also used. There were significant advantages for the treated group on the SIB, ADCS-ADL, and FAST. Sub-analysis of the NPI showed a significant advantage for memantine in the domains of delusions and agitation/aggression. This study was important in showing that a new therapeutic agent different from the cholinergic drugs had a clinically significant effect and that these benefits could be achieved in the more severe stages of the disease. Also crucial when generalizing the trial data to clinical practice was the fact that while there was a clear advantage for the treated patients nevertheless at this advanced stage, all patients were deteriorating. This is important when treating patients clinically when one has no placebo group for reference as one has to consider that despite continued decline, the patient may be getting the benefit of a slowed rate of deterioration.
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