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Memantine


Quick Start: Memantine

Mechanism of action and cognitive benefit

  • Memantine (generic and Namenda extended-release [XR]) has two mechanisms of action: (1) modulating glutamate and (2) enhancing dopamine transmission.

  • It improves attention, alertness, apathy, and global functioning.

Indications and recommendations

  • Memantine (generic and Namenda XR) is approved for patients with moderate to severe Alzheimer’s disease (about Mini-Mental State Examination <15, Montreal Cognitive Assessment <11).

    • Generic memantine is prescribed twice a day, starting at 5 mg QAM, and titrated weekly over four weeks to 10 mg BID.

    • Namenda XR is prescribed once a day, starting at 7 mg QD, and titrated weekly over four weeks to 28 mg QD.

  • Combination therapy—cholinesterase inhibitors plus memantine—gives the best short- and long-term outcomes in patients with moderate to severe Alzheimer’s disease dementia.

Common side effects

  • Common side effects include dizziness, confusion, and drowsiness.

Judging efficacy

  • Memantine improves attention and alertness (not memory per se).

  • To determine whether the medication is working, ask the family and evaluate the patient’s cognition, social engagement, and function two to three months after starting the medication.

Off-label uses

  • Patients with vascular dementia, dementia with Lewy bodies, and Parkinson’s disease dementia may also benefit from memantine, following the same guidelines as for Alzheimer’s disease.

Memantine (Namenda) was approved by the U.S. Food and Drug Administration (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.

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 the most abundant excitatory neural transmitter in the central nervous system, present in about 40% of synapses, and it is critical for 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. 20.1 ).

Fig. 20.1, Possible mechanism of action of memantine (Namenda) at the N -methyl- d -aspartic (NMDA) receptor. (A) Normal physiological function of the NMDA receptor. (i) At rest the presynaptic neuron (left) is filled with glutamate and a magnesium ion blocks the channel of the NMDA receptor on the postsynaptic neuron (right) . Very few glutamate molecules are in the synaptic cleft. (ii) During cognitive activity an action potential (lightning arrow) reaches the presynaptic neuron, (1) glutamate is released from the presynaptic neuron, (2) interacts with the NMDA receptor on the postsynaptic neuron, (3) the magnesium ion pops off, (4) calcium enters the cell, and (5) an action potential (lightning arrow) is generated in the postsynaptic neuron. If we had an electrode measuring the current of the postsynaptic receptor we would find a low level of noise at rest (i), and enough of a calcium signal to rise up above the level of the noise, triggering an action potential in the postsynaptic neuron (ii). (B) Pathological state owing to Alzheimer’s disease. (i) Because of Alzheimer’s disease, cells are dying, releasing their intracellular stores of glutamate, and thus too much glutamate is in the extracellular fluid. Some of this excess glutamate finds its way into the synaptic cleft and interacts with the NMDA receptor, causing the magnesium ion to pop off and calcium to trickle into the cell—even though no action potential has occurred. This trickle of calcium into the cell causes a high level of noise. (ii) Now when an action potential (lightning arrow) reaches the presynaptic neuron (left) , again glutamate is released from the presynaptic neuron and interacts with the NMDA receptor of the postsynaptic neuron (right) . But this time, because the magnesium ion has already popped off and calcium has been trickling into the cell, the signal cannot be detected above the high level of noise, and an action potential cannot be generated. (iii) Additionally, when calcium chronically trickles into cells it is toxic to them, killing the cells. (C) Memantine restores physiological function. (i) The pathological state due to Alzheimer’s disease [same as B(i)]. (ii) Despite there being too much glutamate in the extracellular fluid, stimulating the NMDA receptor, memantine sits in the ion channel—like a “super” magnesium ion—stopping calcium from trickling into the cell, and reducing the noise to a normal, low level. (iii) When the action potential (lightning arrow) reaches the presynaptic neuron on the left and a large amount of glutamate is released, it again interacts with the NMDA receptor of the postsynaptic neuron. Now the memantine molecule pops off just like the magnesium ion and calcium can enter the cell, propagating the action potential (lightning arrow) in the postsynaptic neuron, and physiological function is restored.

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. 20.2 ).

Fig 20.2, Chemical structure of amantadine (Symmetrel [ A ]) and memantine (Namenda [ B ]).

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