Memantine

Medical use

Memantine is approved by the U.S. FDA and the European Medicines Agency for treatment of moderate-to-severe Alzheimer's disease, and has now received a limited recommendation by the UK's National Institute for Health and Care Excellence for patients who fail other treatment options. Within the new guidance memantine is recommended as an option for managing Alzheimer’s disease for people with: moderate Alzheimer’s disease who are intolerant of or have a contraindication to AChE (acetylcholinesterase) inhibitors or those with severe Alzheimer’s disease.

Memantine has been associated with a moderate decrease in clinical deterioration with only a small positive effect 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.

It has shown promising results in studies for treatment of obsessive compulsive disorder, generalized anxiety disorder, as an augmentation therapy for anxiety disorders, ADHD, as well as to help slowing down or even reversing the tolerance development to opioids.

Adverse effects

Memantine is, in general, well-tolerated. Common adverse drug reactions (≥1% of patients) include confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations. Less common adverse effects include vomiting, anxiety, hypertonia, cystitis, and increased libido. It has been reported to induce reversible neurological impairment in multiple sclerosis patients, which led to the halt of an ongoing clinical trial. Though exceedingly rare, extrapyramidal side effects (such as dystonic reactions, etc.) may occur, in particular, in the younger population.

Like many other NMDA antagonists, memantine behaves as a dissociative anesthetic at supratherapeutic doses, and has substituted for phencyclidine in rodent and primate drug discrimination studies. Despite isolated reports, recreational use of memantine is rare due to the drug's long duration and limited availability. Also memantine seems to lack most of the psychoactive effects recreational users are looking for, like euphoria, hallucinations etc.

A recent study demonstrates therapeutically-relevant doses of memantine in the mouse can lead to disruption of cognitive flexibility.

Biochemistry

The drug belongs to a class of drugs called NMDA receptor antagonists, which reduce certain types of brain activity by binding to NMDA receptors on brain cells and blocking the activity of the neurotransmitter glutamate. At normal levels, glutamate aids in memory and learning, but if levels are too high, glutamate appears to overstimulate nerve cells, killing them through excitotoxicity.

Glutamatergic (NMDA receptor)

A dysfunction of glutamatergic neurotransmission, manifested as neuronal excitotoxicity, is hypothesized to be involved in the etiology of Alzheimer's disease. Targeting the glutamatergic system, specifically NMDA receptors, offers a novel approach to treatment in view of the limited efficacy of existing drugs targeting the cholinergic system.

Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors. By binding to the NMDA receptor with a higher affinity than Mg²⁺ ions, memantine is able to inhibit the prolonged influx of Ca²⁺ ions, particularly from extrasynaptic receptors, which forms the basis of neuronal excitotoxicity. The low affinity, uncompetitive nature, and rapid off-rate kinetics of memantine at the level of the NMDA receptor-channel, however, preserves the function of the receptor at synapses, as it can still be activated by physiological release of glutamate following depolarization of the presynaptic neuron. The interaction of memantine with NMDA receptors plays a major role in the symptomatic improvement that the drug produces in Alzheimer's disease. However, there is no evidence as yet that the ability of memantine to protect against NMDA receptor-mediated excitotoxicity has a disease-modifying effect in Alzheimer's, although this has been suggested in animal models.

Serotonergic (5-HT3 receptor)

Memantine acts as a non-competitive antagonist at the 5-HT₃ receptor, with a potency similar to that for the NMDA receptor. The clinical significance of this serotonergic activity in the treatment of Alzheimer's disease is unknown.

Cholinergic (nicotinic acetylcholine receptor)

Memantine acts as a non-competitive antagonist at different neuronal nicotinic acetylcholine receptors (nAChRs) at potencies possibly similar to the NMDA and 5-HT3 receptors, but this is difficult to ascertain with accuracy because of the rapid desensitization of nAChR responses in these experiments. It can be noted that memantine is an antagonist at Alpha-7 nAChR, which may contribute to initial worsening of cognitive function during early memantine treatment. Alpha-7 nAChR upregulates quickly in response to antagonism, which could explain the cognitive-enhancing effects of chronic memantine treatment. 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.

Dopaminergic (D2 receptor)

Memantine acts as an agonist at the dopamine D₂ receptor with equal or slightly higher affinity than to the NMDA receptors.

Sigmaergic (σ1 receptor)

It acts as an agonist at the σ1 receptor with a low K_i of 2.6 µm (2600nm). The consequences of this activity are unclear (as the role of sigma receptors in general is not yet that well understood) and memantine is probably too weak at the sigma binding site to exhibit significant agonist effects, only exhibiting partial agonism or antagonism. Some of memantine's adverse effects arise through this route.

History

Memantine was first synthesized and patented by Eli Lilly and Company in 1968 as an anti-diabetic agent, but it was ineffective at lowering blood sugar. Later it was discovered to have CNS activity, and was developed by Merz for dementia in Germany; the NMDA activity was discovered after clinical trials had already begun. Memantine was first marketed for dementia in Germany in 1989 under the name Axura.

In the US, some CNS activities were discovered at Children's Hospital of Boston in 1995, and Children's licensed patents covering uses of memantine outside the field of ophthalmology to Neurobiological Technologies (NTI) in 1995. In 1998 NTI amended its agreement with Children's to allow Merz to take over development.

In 2000 Merz partnered with Forest to develop the drug for Alzheimers in the U.S. under the name Namenda.

In 2000 Merz partnered with Suntory for the Japanese market and with Lundbeck for other markets including Europe; the drug was originally marketed by Lundbeck under the name Ebixa. It is generic in many countries and is marketed under many brand names worldwide.

Sales of the drug reached $1.8 billion for 2014. The cost of Namenda is $269 to $489 a month.

Research

Memantine is also being tested for neuropathic pain including Complex Regional Pain Syndrome, nystagmus, multiple sclerosis, autism, migraine, schizophrenia, and for protection of cognitive function during whole brain radiation.