Memantine

Memantine is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system by blocking NMDA glutamate receptors. It was first synthesized by Eli Lilly and Company in 1968. Memantine is marketed under the brands Axura and Akatinol by Merz, Namenda by Forest, Ebixa and Abixa by Lundbeck and Memox by Unipharm. Despite years of research, whether memantine has any effect in mild to moderate Alzheimer's disease is unknown.

Biochemistry
The drug belongs to a class of drugs called NMDA receptor antagonists, which help reduce abnormal activity in the brain 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 off key brain cells.

Clinical use
Memantine is approved for treatment of moderate to severe Alzheimer's disease, and has now received a limited recommendation by the UK's National Institute for Clinical 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 in Alzheimer's disease. A systematic review of randomised controlled trials found that memantine has a small positive effect on cognition, mood, behaviour, and the ability to perform daily activities in moderate to severe Alzheimer's disease, but an unknown effect in mild to moderate disease.

Memantine can help patients with severe Alzheimer's disease think more clearly and perform daily activities more easily, but, like other Alzheimer's drugs, it is not a cure and does not stop progression of the disease, the researchers say.

Mild to moderate AD
As of April 2011 new research has emerged that shows this drug is not effective for treatment in stopping the progression of mild to moderate Alzheimers. In a review of 3 studies covering 431 patients with mild AD and 697 with moderate AD - there was no difference in the effectiveness of the drug Memantine. "There were no significant differences between memantine and placebo on any outcome for patients with mild AD, either within any trial or when data were combined," Dr. Lon Schneider of the University of Southern California and colleagues wrote in the Archives of Neurology.

Greg M. Cole, a neuroscientist at the Greater Los Angeles VA Healthcare System and associate director of the Alzheimer's Disease Research Center at the University of California Los Angeles, said that "most of my clinician colleagues are not very impressed with the efficacy of memantine in mild to moderate Alzheimer's disease." Most researchers believe Alzheimer's disease has stages in which the responses to drugs differ, Cole said. "But this distinction is easily lost in the frustration of both lay persons and physicians who want to try whatever might help. So they try memantine in mild Alzheimer's disease cases," he said. "Some mild Alzheimer's disease patients might also respond, but until we can identify subsets of patients who respond well, we have to work with the average responses," Cole added. "Unfortunately, this new study demonstrates that the average response with mild to moderate Alzheimer's disease is marginal at best."

Investigational use
Memantine is also being tested for generalized anxiety disorder, epilepsy, opioid dependence, systemic lupus erythematosus, depression, obsessive compulsive disorder, Tourette Syndrome, problem gambling, attention-deficit hyperactivity disorder (ADHD), glaucoma, tinnitus, neuropathic pain including Complex Regional Pain Syndrome, pervasive developmental disorders, HIV associated dementia, nystagmus, multiple sclerosis, autism and migraine.

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.

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, which forms the basis of neuronal excitotoxicity. The low affinity and rapid off-rate kinetics of memantine at the level of the NMDA receptor-channel, however, preserves the physiological function of the receptor, as it can still be activated by the relatively high concentrations of glutamate released 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. Moreover, 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. Consequently, this may also suggest that administration of nicotine itself may act against the effects of Alzheimer's disease.

Dopaminergic (D2 receptor)
Memantine acts as an agonist at the dopamine D2 receptor.

History
Memantine was first synthesized and patented by Eli Lilly and Company in 1968 (as cited in the Merck Index), and then developed by Merz in collaboration with Neurobiological Technologies, Inc. and licensed to Forest for the U.S. and Lundbeck for selected European and international markets.

Sales of the drug reached $1.2 billion for 2010.