Memantine (Namenda) was approved by the FDA for the treatment of moderate to severe Alzheimer’s disease in 2003. In 2014 twice-daily Namenda was discontinued, once-daily Namenda extended-release (XR) was introduced, and sometime later twice-daily memantine became available as generic. Memantine has become the second most widely used drug after donepezil (Aricept) to treat Alzheimer’s disease. Much of what we have discussed regarding the cholinesterase inhibitors also pertains to memantine (generic and Namenda XR). But, in addition to a different mechanism of action, there are also important differences between memantine and the cholinesterase inhibitors in terms of which patients are most likely to benefit, how the drug is administered, and its side effect profile. We will also discuss how memantine (generic or Namenda XR) can be combined with cholinesterase inhibitors.
|Mechanism of action and cognitive benefit|
|Indications and recommendations|
|Common side effects|
Mechanism of Action
Memantine has an entirely different mechanism of action than the cholinesterase inhibitors. There are, in fact, at least two mechanisms of action for memantine that may be clinically relevant: modulating glutamate and enhancing dopamine transmission.
Modulating Glutamate Transmission
Memantine acts on neurons that use glutamate as a neural transmitter. Glutamate is one of a group of neural transmitters known as amino acid neural transmitters. Other amino acid neural transmitters include GABA, aspartame, and others, although glutamate is the most abundant in this group. In fact, glutamate is the most abundant excitatory neural transmitter in the central nervous system, and it is present in about 40% of synapses. Like acetylcholine, glutamate is also very important in learning and memory. Numerous preclinical studies conducted in animals have shown that, when glutamate synapses are blocked, new memories cannot be formed ( ). Additionally, there is evidence that the amnesia produced in humans from anoxia (e.g., oxygen deficiency due to cardiac arrest) is the result of the death of glutamatergic neurons.
When glutamate is released from the presynaptic neuron, it crosses the synapse and affects one or a number of different kinds of receptors on the postsynaptic neuron. One of these is the N -methyl- d -aspartic acid (NMDA) receptor. The NMDA receptor appears to be the crucial receptor in the formation of new memories. Memantine acts by regulating the NMDA receptor ( Fig. 17-1 ).
Enhancing Dopamine Transmission
In addition to its effects at the NMDA receptor, there is also much evidence that memantine is a dopamine agonist. It stimulates dopamine receptors in vitro ( ), increases dopaminergic function in animal models ( ), and patients with Parkinson’s disease show improvement in their parkinsonian symptoms ( ). Why memantine has this effect is not entirely clear, but it is structurally similar to amantadine (Symmetrel), which is a known dopamine agonist used to treat patients with Parkinson’s disease ( Fig. 17-2 ).
Which Patients Should Take Memantine (Generic and Namenda XR)?
Memantine has been approved in Europe for the treatment of vascular dementia since the 1980s. The initial research using memantine for Alzheimer’s disease was begun in the mid-1990s. Unlike the cholinesterase inhibitors, which are FDA-approved for patients with mild, moderate, and severe Alzheimer’s disease dementia, memantine is FDA-approved only for patients in the moderate to severe stages of the disease (about Mini-Mental State Examination [MMSE] score <15 and Montreal Cognitive Assessment (MoCA) score <11). Clinical trials in this stage of disease have shown that the magnitude of the benefit of the drug is comparable to that seen with cholinesterase inhibitors ( ), although there have been no head-to-head studies. Memantine has also been shown to benefit Alzheimer’s disease dementia patients who are residing in nursing homes ( ).