Memantine

Mechanism of Action^

According to a theory known as the excitotoxicity theory, lower energy levels in the nerve cells of people with HD cause them to be overly sensitive to glutamate. As a result, even normal levels of glutamate can overactivate the glutamate receptors on the nerve cells. When these receptors (also known as NMDA receptors) are activated, calcium ions enter the nerve cells. Excessive activation causes a buildup of these calcium ions, which then leads to the death of the nerve cell. (For more on the excitotoxicity theory, click here.)

HD researchers believe that memantine may have strong potential to slow the progression of HD by decreasing the NMDA receptor´s sensitivity to glutamate. Memantine is an NMDA antagonist. As an antagonist, memantine prevents the excessive binding of glutamate to NMDA receptors, inhibiting the pathway to excessive NMDA activation and nerve cell death. Memantine is also a non-competitive antagonist. “Non-competitive” means that memantine binds to a site on the NMDA receptor that is different from glutamate´s binding site. By binding to one portion of the NMDA receptor, memantine changes the overall shape of the receptor, making it more difficult for glutamate to bind to the other portion of the receptor.

Memantine differs from other NMDA non-competitive antagonists in that it allows the NMDA receptor to undergo physiological activity required for normal nerve cell functioning, while at the same time preventing the receptor from the over-activation that leads to nerve cell death. This is important because NMDA receptors still need to be activated to allow the entry of calcium ions, which facilitate learning and memory. But once again, too much activation of the receptor can lead to nerve cell death. Two properties of memantine allow the NMDA receptors to be activated to the optimal level, which allows learning but prevents nerve cell death.

The first property of memantine prevents nerve cell death by decreasing the NMDA receptor´s sensitivity to glutamate. When glutamate binds to the receptor, it increases the cell´s electrical charge. The electrical charge inside the cell first needs to rise to a specific value before the magnesium ion leaves the receptor so that calcium can now enter. In people with HD, the over-excitation by glutamate causes the magnesium ion to leave too easily, allowing the influx of calcium ions responsible for nerve cell death. On the other hand, memantine is not as sensitive as the magnesium ion towards an electrical charge. That is, more glutamate needs to bind to the receptor before memantine will leave the receptor, thereby allowing calcium ions to enter. This is an advantage for those with HD, because memantine can block the pathological pathway by not responding as easily to an excessive amount of glutamate.

Besides inhibiting over-activation by glutamate, the second property of memantine still enables the physiological pathway to learning and memory. Memantine has “fast blocking/unblocking kinetics.” This means that, after glutamate strongly activates the receptor, memantine is still capable of quickly unbinding the receptor, thereby allowing calcium to enter the nerve cell. The fast kinetics of memantine is what allows an appropriate amount of calcium to enter the nerve cell, a process necessary for learning and memory.

Memantine has been clinically used in the treatment of dementia and Alzheimer´s disease. In studies general to all chronic neurodegenerative diseases, therapeutic doses of memantine inhibit disruption of spatial learning and aid learning in general through prevention of the pathological pathway discussed earlier. Researchers are currently testing its efficacy in treating other CNS disorders, including HD. Discussed later in this article, a clinical study on treatment of HD with memantine has also discovered benefits in its ability to slow the progression of HD.

Clinicians have used memantine to treat over 200,000 patients for mostly dementia over the last fifteen years. Although memantine has been well-tolerated in humans, in animals it has produced side effects characteristic of other NMDA receptor antagonists. For instance, memantine can impair the ability to control muscular movements (ataxia), muscle relaxation (myorelaxation), and is sometimes known to cause amnesia. However, these side effects were only seen at high dosages (greater than or equal to 20mg/kg per day)-dosages far higher than the usual 5mg/kg per day used in humans for therapy. In humans, high doses of memantine have been known to result in psychosis in some rare instances. At therapeutic (low-level) doses, memantine does not display the negative side effects found in other NMDA receptor antagonists.

Other tested side effects are drug dependency and abuse. There is some evidence to show that memantine can lead to dependence in animals. A dependency on memantine appeared in rats and monkeys but only at high doses. However, researchers have widely agreed that memantine has little abuse potential based on the many years it has been clinically used, recent clinical studies, and zero reports of abuse in humans.

Research on Memantine^

Beister, et al. (2004) conducted a two-year-long study with twenty-seven HD patients recruited from two different clinics. Each patient took up to a maximum of 30mg of memantine per day, depending on his/her individual tolerance for the drug. (Note: mg/day should not be confused with the units mg/kg per day that was used to specify therapeutic-level doses.)

Rating scales established in the HD medical literature measured the progression of HD. The Scale of Abnormal Involuntary Movements, the HD Rating Scale, and standardized video recordings evaluated chorea. For instance, in the videotapes, chorea was measured for the arms, legs, head, and trunk each on a three point scale, with 1 = slight, 2 = moderate, 3 = severe, and half-points possibly assigned. The scores for the different body parts were then averaged together.

The Clinical Global Impression (CGI) scale, the HD Activities of Daily Living (HD-ADL) scale, and the Total Functioning Capacity (TFC) of the HD Functional Capacity Scale were used to measure deteriorations. For example, HD-ADL consists of seventeen items that track the progress of HD through assessing a person with HD´s capabilities in taking care of him/herself in various areas, such as eating, dressing, taking medicine, and maintaining relationships. The person´s capability in each area is evaluated on a 3 point scale, with 0 indicating normal ability and 3 indicating necessary help from others required. The points for each area are summed to get the total HD-ADL score.

The Total Motor Score of the Unified HD Rating Scale (UHDRS) measured motor functioning. The Total Motor Score is reached by summing up points for certain movements, such as being able to carry out a sequence of hand movements or the velocity in moving a certain way. Scores for each movement are graded on a 4 point scale, with 0 being normal and 4 being unable to execute.

Psychometric tests, such as the Short Syndrome Test (SKT), the Brief Test of General Intelligence (KAI), and the Trail-making test were used to measure cognitive abilities.

The results following a two year treatment with memantine suggest that memantine has the ability to slow the progression of HD. Untreated people with HD in the Huntington Study Group (1996) experienced a 21.2% decrease in motor function over two years according to the Total Motor Score of the UHDRS. In comparison, treated patients experienced a decline of only 4.3%.

The scores on competence in daily living tasks also show memantine´s benefits. Researchers compared their results measured by HD-ADL with results measured by TFC of the HD Functional Capacity Scale because the two are similar enough to produce comparable outcomes. Untreated people with HD had a decrease in ability of daily living tasks, demonstrated by their average decline of 0.5 points over six months on the TFC scale. On the other hand, people with HD who received memantine treatment actually gained ability in daily living tasks, with an average increase of 0.28 points. These results translate to a 15.4% decrease in competency of daily living tasks over two years in untreated people with HD but a 9.3% reduction in progression of incompetence in daily living tasks in treated people with HD.

With no statistically significant changes in SKT and KAI, psychometric testing showed no deterioration of cognition in the treated participants.

Furthermore, in the second year of treatment (between 12 and 24 months), there were no significant changes in CGI and HD-ADL scores. This score stability indicates a reduction in progression of deterioration. It also interestingly suggests that memantine´s ability to prevent HD progression is expressed only after long treatment with memantine.

Overall, the researchers concluded that memantine has good potential to slow the progression of HD. However, more studies need to be conducted with control groups to serve as a comparison (control groups do not get treatment, they take a placebo) in order to verify the study´s findings.

Forest Pharmaceuticals, Inc. (2010) ran a phase II clinical trial in which 50 people with mild to moderate Huntington’s disease received either 10 mg of memantine or a placebo twice daily for 12 weeks. Then, for the next 12 weeks, all participants took memantine. When compared to patients taking placebo, patients taking memantine showed improvements on tests of memory and attention, but performed worse on tests measuring motor symptoms. Larger studies will be necessary to confirm these findings.

For further reading^

1. Beister, et al. “The N-methyl-D-asparate antagonist memantine retards progression of Huntington´s disease.” Journal of Neural Transmission Supplement. 2004 Supplement; (68): 117-22.
   This fairly technical article presents the complete details of the study conducted by Beister, et al. The article concludes that memantine has good potential to slow the progression of HD, but more studies still need to be conducted to confirm results.
2. Parsons, et al. “Memantine is a clinically well tolerated N-methyl-D-asparate (NMDA) receptor antagonist-a review of preclinical data.” Neuropharmacology. 1999, Jun; 38(6): 735-67. Review.
   This is a highly technical article that summarizes the findings on memantine in its usage for a variety of diseases, including HD. The article also explains in detail memantine´s mechanism and tolerability.
3. www.memantine.com
   This website is easy to understand but centers on memantine´s use for Alzheimer´s disease. However, the website clearly explains memantine´s mechanism as well as provides many research studies. The research posted under “Studies & Literature” is helpful in understanding more about memantine´s effects and good tolerability.
4. Palmer GC. “Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies.” Current Drug Targets. 2001 Sep; 2(3): 241-71. Review.
   This is a highly technical article that reviews memantine´s mechanism against glutamate toxicity. It is not very useful in understanding memantine´s effects on HD in particular.
5. Proc. of Fourth Annual Huntington Disease Clinical Research Symposium, San Pavilion Ballroom at the Hyatt Regency La Jolla at Aventine, San Diego. This technical report describes the results of the phase II clinical trial on memantine