Memantine – Mechanism of Action | Psychopharmacology | Clinical Application

MECHANISMS OF ACTION OF MEMANTINE

Glutamate is an excitatory neurotransmitter involved in learning, memory, and neuronal plasticity, primarily in cortical and hippocampal regions.

Glutamate activates three principal types of glutamate receptors (GluRs):

• α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors  (AMPARs)/kainate receptors
• N-methyl-D-aspartate (NMDA) receptors (NMDARs)
• Metabotropic glutamate receptors (mGluRs)

The primary type of glutamate receptors (GluRs) is the ionotropic GluR (iGluRs) – AMPARs / KainateRs and NMDARs.

AMPARs and NMDARs mediate fast synaptic transmission in the basal ganglia. [Götz et al., 1997]

The activation of AMPARs provides the initial depolarization that leads to NMDARs activation.

Activation of NMDARs also regulates the function of AMPA receptors (AMPARs). [See Intranasal Esketamine – Psychopharmacology, Side effects and Clinical Application]

Long-term potentiation (LTP) and Long-term depression (LTD): 

Glutamate binds to the NR2 subunit of the NMDARs.

• The activation of postsynaptic NMDA receptors in hippocampal pathways controls long-term potentiation (LTP), a process of enduring changes in synaptic strength leading to long-lasting increases in synaptic transmission. [Glasgow et al., 2017]
• On the other hand, long-term depression (LTD) is a process of long-lasting decrease in the efficiency of synaptic transmission, particularly synaptic transmission that is mediated by the synaptic activation of AMPARs.

Location of NMDARs:

NMDARs are situated in synaptic and extrasynaptic areas across several brain regions. [Hardingham and Bading, 2010]

• Extrasynaptic NMDA receptors link with axons and glia.
• Synaptic NMDARs activation promotes neuronal health

Chronic activation of extrasynaptic NMDARs leads to neurotoxicity.

A shift in the balance from synaptic towards extrasynaptic NMDAR signalling (i.e., excitotoxicity) is implicated in the pathogenesis of AD and other neuropathological disorders such as Parkinson’s, Huntington’s, and multiple sclerosis. [Bleich et al. 2003]

Memantine, through its low-affinity inhibition of the NMDA receptor, targets the glutamatergic system and inhibits excessive glutamatergic activity:

• Memantine binds more effectively than Mg+ ions at the NMDA receptor. It antagonises the prolonged influx of Ca+ ions through the NMDA channel (due to excessive glutamate levels, which counter the voltage-dependent block of NMDA receptors by Mg+ ions) whilst preserving the transient physiological activation of the channels by higher concentrations of synaptically released glutamate.
• The control of intracellular Ca²⁺ concentration is essential for neurons, as it determines their survival and physiological function.
• As memantine is voltage-dependent, it dissociates in the context of an average physiological signal, and normal transmission proceeds.
• Thus, memantine’s non-competitive nature means that it does not interfere with the physiological activity of glutamate, which is necessary for normal brain functioning.
• Memantine inhibits extrasynaptic NMDARs (chronic activation leads to neurotoxicity) more potently than synaptic NMDARs minimising excitotoxicity but maintaining normal synaptic transmission.
• Memantine’s unique and favourable off-rate from the NMDA receptor channel determines its clinical efficacy and tolerability. A slower off-rate would cause the drug to accumulate and interfere with normal neurotransmission, whereas a faster off-rate would be ineffectual.

Difference between Memantine and Ketamine: [Bartsch and Nordman, 2022]

Receptor specificity

• Memantine (not ketamine) inhibits extrasynaptic NMDARs (associated with excitotoxicity) more effectively than synaptic NMDARs. [Glasgow et al., 2017]
• Ketamine inhibits both synaptic and extrasynaptic NMDARs.
• Ketamine is non-selective for the NMDAR, binding to muscarinic, monoaminergic, and opioid receptors which may mediate the psychomimetic effects of ketamine.   Ketamine and Esketamine in Depression – A Synopsis on Efficacy and Mechanism of Action

Affinity:

• Memantine binds to the NMDA receptor with moderate affinity as opposed to ketamine.

NR1 vs NR2 Binding:

• NR2A containing NMDARs are required for LTP.
• NR2B-containing NMDARs are required for LTD. Thus, the antagonism of NR2B-containing NMDARs blocks LTD.
• Memantine inhibits GluNR1/2A (but not GluNR1/2B) receptors more effectively during long than brief exposures to glutamate.
• Ketamine inhibits GluNR1/2B (but not GluNR1/2A) receptors more effectively during brief than long exposures to glutamate;
• Memantine slows recovery from GluNR1/2A (but not GluNR1/2B) receptor desensitisation.
• Ketamine speeds recovery from GluNR1/2B (but not GluNR1/2A) receptor desensitisation.
• Memantine stabilises a Ca2+ – dependent desensitised state of GluNR1/2A receptors, which enhances tolerability.
• Ketamine reduces the Ca2+ – dependent desensitised state of GluNR1/2B receptors leading to decreased inhibition of Ca2+ release (excitotoxic state).

Duration of binding: 

• Ketamine binds to the NMDARs for more extended periods than memantine which mediates the more persistent effects of ketamine on pain and antidepressant activity.
• This may explain ketamine’s high and memantine’s low sedative and psychotomimetic effects.

Clinical Relevance:

• Ketamine inhibits plasma membrane Ca2+ ATPase (PMCA) as a general phenomenon that contributes to Ca2+ homeostasis dysregulation via interfering with Ca2+ clearance, which may induce a feedback response leading to long-lasting increases in presynaptic glutamate secretion.
• This aberrant glutamatergic neurotransmission may, in turn, produce an aberrant signal leading to the generation of psychotic-like effects and potential excitotoxicity. [Lisek et al.,2017]
• Ketamine also disinhibits pyramidal neurons in the medial prefrontal cortex (mPFC) and the CA1 region of the hippocampus by inhibiting GABAergic interneurons in both areas mediated by ketamine’s higher affinity for GluNR2B-containing NMDARs expressed in PFC somatostatin interneurons and GluNR2 -containing NMDARs preferentially expressed in CA1 hippocampal interneurons. [Bartsch and Nordman, 2022]

PHARMACOKINETICS OF MEMANTINE

Trade names: Memanxa, Namenda, Ebixa.

• Oral memantine solution is well absorbed in the GI tract and has linear pharmacokinetics, with peak blood levels occurring approximately 7 hours after dosing.
• Memantine undergoes tubular excretion and has an elimination half-life of 60 to 80 hours with up to 80% unchanged in the urine. The remaining ~20% is metabolised into three polar metabolites with little to no activity; the hepatic CYP450 enzyme system only partially contributes to the metabolism of Memantine. [Product information Memantine]

DOSING OF MEMANTINE

The recommended maintenance dose is 20 mg per day. The tablets come in 10 mg and 20 mg doses.

Memantine can be administered in the morning or nighttime.

Memantine shows sleep-promoting properties by reducing fragmented sleep and improving Behavioural and Psychological Symptoms of Dementia (BPSD). [Ishikawa et al., 2016]

Memantine may also decrease probable REM sleep behaviour disorder in patients with DLB and PDD. [Larsson et al., 2010]

Titration regime:

• 5 mg per week.

Week 1 (day 1 – 7): 

• 5 mg (½ x 10 mg tablet) OD.

Week 2 (day 8 – 14) :

• 10 mg OD

Week 3 (day 15 – 21) :

• 15 mg OD.

From Week 4 :

• The recommended maintenance dose is 20 mg OD.

SIDE EFFECTS AND DRUG INTERACTIONS OF MEMANTINE

Memantine is well tolerated in doses up to 20 mg/day with dizziness, headache, confusion, and constipation, the most common adverse events reported in clinical trials. [Blanco-Silvente et al., 2018]

Other less common side effects reported in the product information include: [Product Information Memantine]

Pain, abnormal crying, influenza-like symptoms, leg pain, syncope, dependent oedema, hypertonia, gastroenteritis, bradycardia, hyperuricaemia, hypertension, and hypokalaemia.

Drug interactions

• As most memantine is excreted unchanged, an interaction with CYP450 enzymes is unlikely, with no inhibition of these enzymes previously reported.
• As memantine is eliminated by tubular secretion, drugs that make the urine more alkaline (e.g., carbonic anhydrase inhibitors) can reduce memantine clearance by approximately 80%, thus resulting in memantine accumulation.
• Concomitant use of NMDA antagonists such as amantadine, ketamine or dextromethorphan should be avoided due to side effect potentiation based on action at the NMDA receptors.

CLINICAL EVIDENCE

Although memantine is indicated for patients with moderate-to-severe AD symptoms, it is also often prescribed for patients with mild-to-moderate symptoms.

Memantine is efficacious in treating AD (including moderate to severe) when used alone compared to a placebo. [Kishi et al., 2017]

Glutamatergic neurons in the cortex, amygdala, and hippocampus connect with forebrain cholinergic neurons and, as such, are susceptible to glutamate excitotoxicity.

The combination of memantine and an acetylcholinesterase inhibitor (AChEI) is suggested to be complementary due to their respective effects on the glutamatergic and cholinergic signalling systems. [Parsons et al. 2013]

Combination therapy safety:

• No known pharmacokinetic interactions between memantine and AChEIs, with combination therapy shown to be well tolerated. [Howard et al. 2012]
• Some adverse events, such as agitation and GI-related side effects, were reduced. [Atri et al. 2013]

Combination therapy efficacy:

• Combination therapy with acetylcholinesterase inhibitors (AChEIs) shows benefits in moderate-to-severe Alzheimer’s disease in terms of cognition, behavioural disturbances, activities of daily living, and global assessment. The combination was also well tolerated. [Matsunaga et al., 2015]
• Memantine plus AChEIs showed a significant reduction in BD and improvement in cognitive function compared with AChEIs alone in moderate to severe AD. [Kishi et al., 2017]
• Compared to monotherapy, superior improvements in cognitive, functional, and behavioural scores have been reported. [Tariot et al 2004]; [van Dyck et al 2006]

AD with agitation, aggression and psychosis: 

• Memantine may be a safe and effective treatment in Alzheimer’s disease patients with agitation/aggression or psychosis. [Wilcock et al., 2008]
• Memantine also has benefits in treating behavioural disturbances in patients with Alzheimer’s disease. [Kishi et al., 2017]

Borderline Personality Disorder: 

• Memantine at a 20 mg daily dose can improve BPD symptomatology and is well tolerated. [Kulkarni et al., 2018]

Pain syndromes: 

• Useful adjunct when used early in the initial phases of phantom limb pain or soon after surgery on opioid-tolerant subjects. [Buvanendran and Kroin, 2008]
• Memantine (10 mg/day and 20 mg/day) reduced spontaneous pain, mechanical and cold allodynia, mechanical hyperalgesia, and wind-up–like pain in patients with postherpetic neuralgia. [Eisenberg et al., 1998]

PTSD: 

• Memantine significantly reduced PTSD symptoms in civilian female PTSD patients, and the drug was well tolerated. Its pre-post effect size is 1.35, almost comparable to trauma-focused CBT. [Hori et al., 2021]
• Memantine improved cognitive symptoms, PTSD symptoms, and mood in veterans with PTSD. [Ramaswamy et al., 2015]

Schizophrenia: 

• Add-on treatment with memantine may improve negative and cognitive symptoms, particularly the negative symptoms of schizophrenia. [Kikuchi, 2020]

Trichotillomania and skin-picking disorder: 

• A double-blind placebo-controlled trial showed that Memantine treatment was highly efficacious in reducing hair-pulling and skin-picking symptoms compared with placebo, with an NNT of 1.9. [Grant et al., 2023]. 

SUMMARY

Memantine was approved for the treatment of dementia due to its efficacy in minimising the overactivation of NMDA receptors and reducing neurotoxicity.

Its clinical tolerability is a function of its unique and favourable pharmacodynamics on the NMDA receptor associated ion-channel.

As glutamate plays a role in other disorders such as pain, schizophrenia, and PTSD, memantine shows some benefits in these disorders.