Memantine

Memantine, sold under the brand name Namenda among others, is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth. Common side effects include headache, constipation, sleepiness, and dizziness. Severe side effects may include blood clots, psychosis, and heart failure. It is believed to work by acting on NMDA receptors, working as a pore blocker of these ion channels. Memantine was first discovered in 1963. It was approved for medical use in Germany in 1989, in the European Union in 2002, and in the United States in 2003. It is available as a generic medication. In 2023, it was the 145th most commonly prescribed medication in the United States, with more than 3 million prescriptions.

Memantine, sold under the brand name Namenda among others, is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth. Common side effects include headache, constipation, sleepiness, and dizziness. Severe side effects may include blood clots, psychosis, and heart failure. It is believed to work by acting on NMDA receptors, working as a pore blocker of these ion channels. Memantine was first discovered in 1963. It was approved for medical use in Germany in 1989, in the European Union in 2002, and in the United States in 2003. It is available as a generic medication. In 2023, it was the 145th most commonly prescribed medication in the United States, with more than 3 million prescriptions. ===Alzheimer's disease and dementia=== Memantine is used to treat moderate-to-severe Alzheimer's disease, especially for people who are intolerant of or have a contraindication to AChE (acetylcholinesterase) inhibitors. One guideline recommends memantine or an AChE inhibitor be considered in people in the early-to-mid stage of dementia. Memantine has been associated with a modest improvement; with small positive effects on cognition, mood, behavior, and the ability to perform daily activities in moderate-to-severe Alzheimer's disease. There does not appear to be any benefit in mild disease. Memantine when added to donepezil in those with moderate-to-severe dementia resulted in "limited improvements" in a 2017 review. The UK National Institute for Clinical Excellence (NICE) issued guidance in 2018 recommending consideration of the combination of memantine with donepezil in those with moderate-to-severe dementia. Memantine is an uncompetitive NMDA receptor antagonist, with an IC50 binding affinity of ~500-1,000 nM (0.5-1 μM), but displays higher potency at extrasynaptic NMDA receptors (IC50 = ~22 nM), suggesting preferential inhibition of pathological glutamatergic signaling. Memantine also exhibits activity at several other receptors: Dopamine D 2 High receptor agonist (IC50 affinity = ~137-917 nM); increases dopaminergic activity in the prefrontal cortex and striatum. Memantine may inhibit the release of prolactin through D2 agonism, based on studies from isolated anterior pituitary cells. Alpha 7 nicotinic acetylcholine receptor antagonist (IC50 affinity = 340nM-5,000 nM or 0.34-5 μM). 5-HT 3 receptor receptor antagonist (IC50 affinity = ~1,000 nM). Believed to block NMDA overactivation and restore cognitive dysfunction without significantly impairing normal synaptic transmission. No meaningful acetylcholinesterase (AChE) inhibition. Memantine acts as a non-competitive antagonist at the α 7 nicotinic acetycholine receptor (IC50 affinity = 340nM-5,000nM or 0.34-5 μM). Several studies have observed that Memantine's antagonism at nAChRs is higher than both its affinity to NMDA and 5-HT 3 receptors, but this may be difficult to ascertain with accuracy due to rapid desensitization of nAChRs. Antagonism of α 7 nAChRs may contribute to the initial worsening of cognitive function during early Memantine treatment. Nicotinic acetylcholine receptor, specifically α 7 nAChR, upregulate quickly in response to antagonism, which could explain the possible cognitive-enhancing effects of Memantine. It has been shown that the number of nicotinic receptors in the brain are reduced in Alzheimer's disease, even in the absence of a general decrease in the number of neurons, and nicotinic receptor agonists are viewed as interesting targets for anti-Alzheimer drugs. Memantine has been shown to act as an agonist of dopamine D 2 High receptor with equal or slightly higher affinity than to NMDA receptors (D2 IC50 affinity = ~137-917 nM). In another study, Memantine was shown to increase dopaminergic activity in the prefrontal cortex and striatum of mice. At least one study questions the relevance of Memantine's D 2 receptor action, suggesting a low Ki value. Memantine acts as a weak agonist of the sigma σ 1 receptor with low affinity (K i = 2,600nM or 2.6 μM). Due to this low affinity, therapeutic concentrations of memantine are most likely too low to have any sigmaergic effect as a typical therapeutic dose is 20 mg. The consequences of sigma activity would be unclear, as the role of sigma receptors in general is currently not very well understood. However, excessive doses of memantine taken for recreational purposes, which are many times greater than prescribed doses, may indeed activate this receptor. ===Brand names=== As of August 2017, memantine is marketed under many brand names worldwide including Abixa, Adaxor, Admed, Akatinol, Alceba, Alios, Almenta, Alois, Alzant, Alzer, Alzia, Alzinex, Alzixa, Alzmenda, Alzmex, Axura, Biomentin, Carrier, Cogito, Cognomem, Conexine, Cordure, Dantex, Demantin, Demax, Dementa, Dementexa, Ebitex, Ebixa, Emantin, Emaxin, Esmirtal, Eutebrol, Evy, Ezemantis, Fentina, Korint, Lemix, Lindex, Lucidex, Manotin, Mantine, Mantomed, Marbodin, Mardewel, Marixino, Maruxa, Maxiram, Melanda, Memabix, Memamed, Memando, Memantin, Memantina, Memantine, Mémantine, Memantinol, Memantyn, Memanvitae, Memanxa, Memanzaks, Memary, Memax, Memexa, Memigmin, Memikare, Memogen, Memolan, Memorel, Memorix, Memotec, Memox, Memxa, Mentikline, Mentium, Mentixa, Merandex, Merital, Mexia, Mimetix, Mirvedol, Modualz, Morysa, Namenda, Nemdatine, Nemedan, Neumantine, Neuro-K, Neuroplus, Noojerone, Pertam, Polmatine, Prilben, Pronervon, Ravemantine, Talentum, Timantila, Tingreks, Tonibral, Tormoro, Valcoxia, Vilimen, Vivimex, Witgen, Xapimant, Ymana, Zalatine, Zemertinex, Zenmem, and Zimerz. It is marketed in some countries as a combination drug with donepezil (memantine/donepezil) under the brand names Namzaric, Neuroplus Dual, and Tonibral MD. Memantine does not appear to be effective in the treatment of unipolar major depression or bipolar depression on the basis of systematic reviews and meta-analyses, including a 2021 Cochrane review. However, a 2022 systematic review and meta-analysis concluded that memantine was significantly effective in the treatment of depressive symptoms in various psychiatric disorders, although with a very small effect size (Hedges' g = -0.17). There are likewise limited data to support memantine in the treatment of schizophrenia based on systematic reviews and meta-analyses. However, a 2019 systematic review and meta-analysis reported that memantine was effective in the treatment of the negative and cognitive symptoms of schizophrenia with medium to large effect sizes. === Autism spectrum disorder=== There is no evidence that memantine improves symptoms of autism spectrum disorder. A 2024 meta-analysis of NMDA antagonists (including memantine) found no benefit over placebo on core or associated symptoms and more adverse events, while a 2022 review concluded the effect on core symptoms is uncertain.

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