Revisiting Memantine: NMDA Modulation and Its Growing Relevance in Seizure Care

Epilepsy treatments are typically used specifically for seizure disorders, but emerging research has explored whether certain agents used in neurodegenerative diseases may also have anticonvulsant potential. One such medication is memantine (Namenda; AbbVie), which is primarily approved for the treatment of moderate-to-severe Alzheimer disease (AD). Through analysis of its mechanism of action, memantine appears to influence pathways implicated in seizure generation, leading to growing theoretical and clinical interest in its potential role in epilepsy.

Memantine functions as a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor.¹ Under normal physiologic conditions, activation of NMDA receptors by glutamate allows controlled calcium influx into neurons, supporting synaptic plasticity and memory formation. However, in AD, chronic glutamatergic stimulation leads to excessive calcium entry, neuronal excitotoxicity, and progressive neurodegeneration.² Memantine mitigates this process by blocking excessive NMDA receptor activation while preserving normal physiologic signaling. This neuroprotective effect is central to its therapeutic benefit in AD.¹

Interestingly, excessive glutamatergic activity and NMDA receptor overactivation are also key contributors to epileptogenesis.³ In disorders such as Mesial temporal lobe epilepsy, activation of NMDA receptors on hippocampal pyramidal neurons is associated with upregulation of NMDA receptor subunits such as NR2B and NR2D.⁴ These molecular alterations can enhance neuronal excitability and contribute to sustained seizure activity. Because memantine reduces NMDA-mediated calcium influx, it is theoretically capable of lowering excitatory neurotransmission and reducing seizure propagation.¹

Clinical observations provide additional support for this hypothesis. One reported case involved an 85-year-old man with advanced AD who developed 2 focal seizures after abrupt discontinuation of memantine.⁵ Although this does not establish causation, the temporal relationship suggests that removal of a NMDA receptor blockade may have lowered the seizure threshold, possibly due to rebound glutamatergic hyperexcitability. This observation supports the concept that memantine may modulate neuronal excitability beyond its cognitive effects.

Further evidence comes from genetic epilepsy research. Mutations in the GRIN2A gene, which encodes a subunit of the NMDA receptor, have been associated with epileptic spasms and other refractory seizure disorders.⁶ In one case, a 3-year-old boy with epileptic spasms did not see success with multiple antiseizure medications, including vigabatrin (Sabril; Lundbeck), topiramate (Topamax; Janssen Pharmaceuticals), phenobarbital (Luminal; Bayer), clonazepam (Klonopin; Roche), and levetiracetam (Keppra; UCB). Genetic testing revealed a GRIN2A mutation, prompting the initiation of memantine at 0.15 mg/kg/day with gradual titration to 1 mg/kg/day. Following treatment, the patient experienced significant seizure reduction and ultimately became seizure-free.⁷ This case highlights the emerging role of precision medicine, in which targeting the specific molecular defect—NMDA receptor dysfunction—can produce meaningful clinical benefit.

A prospective cohort study involving 178 participants with seizures also compared memantine and non–memantine groups.⁸ Of the 85 patients receiving memantine, no new-onset generalized tonic-clonic seizures were reported during follow-up, whereas 1 episode of status epilepticus occurred in the non–memantine group.⁸ Although observational and not definitive, these findings suggest a potential protective signal.

Overall, memantine’s NMDA receptor antagonism provides a biologically plausible mechanism for seizure modulation. Although it is not currently approved or guideline-recommended for epilepsy treatment, accumulating theoretical, genetic, and observational data suggest it may have a niche role in selected patients, particularly those with NMDA receptor–related pathophysiology. Pharmacists should be aware of emerging evidence surrounding NMDA receptor modulation in seizure disorders, particularly in patients with coexisting AD and epilepsy.

About the Author

Snehal Desai, PharmD, is an assistant pharmacy manager with Publix Super Markets.

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