Week of January 13 - January 19, 2008

AMSTERDAM – A study published this month in the Journal of Alzheimer’s Disease found that the drug memantine (trade names: Namenda, Axura, Ebixa), praised as “the first and only representative of a new class of Alzheimer’s drugs” actually works in ways similar to other compounds. Moreover, researchers at the University of Aberdeen said memantine is beneficial only in a narrow concentration range.  Its complex profile requires careful dosage adjustment and makes it suitable for certain patients more than others.

This means doctors need to exercise extra caution when considering what dose to prescribe.  Patients and caregivers should pay close attention to any side effects they notice and notify the doctor immediately.

Alzheimer’s disease, which affects approximately one out of every five people over the age of 80, involves the failure of two “messenger” brain chemicals necessary for the communication of brain cells.

The stimulatory brain messenger acetylcholine is down-regulated, while over-activation of the messenger glutamate leads to the death of neurons.

The first generation of compounds which were aimed at boosting the brain’s acetylcholine levels led to the development of drugs such as Aricept (donepezil) and Exelon (rivastigmine).

For a long time, attempts by a considerable number of pharmaceutical companies and researchers to develop drugs that could block the action of glutamate were unsuccessful since these receptors are also required for normal brain function, learning and memory in particular.

It was therefore considered a major breakthrough when memantine was discovered to have beneficial effects in Alzheimer’s disease, not affecting the normal function of glutamate signaling but rather only affecting the excessive actions leading to cell death.

Memantine was approved in 2002 by the European Agency for the Evaluation of Medicinal products (EAEM) and a year later, in 2003 by the US Food and Drug Administration (FDA) for the treatment of moderate-to-severe Alzheimer’s disease.

Its arrival on the market was greeted with great expectations since it could potentially be beneficial not only in the treatment of Alzheimer’s disease, but also for other brain disorders that involve excess glutamate stimulation, such as trauma and stroke.

In the University of Aberdeen study, however, researchers report this month that memantine has a much more complex pharmacological profile than originally described.  

In fact, it indeed works in a way similar to the originally introduced drugs that affect acetylcholine-related signaling in addition to weak actions on glutamate, and it has a negative effect on neuronal communication at high concentrations.

At lower concentrations, memantine was able to enhance signaling between neurons in the hippocampus (the main area of the brain affected in Alzheimer’s disease) and was able to reverse learning and memory deficits.

However, a pharmacological analysis showed that this was not due to its ability to block glutamate signaling, but was instead due to an additional and more potent action on the acetylcholine system.

Thus, the findings confirm that memantine shows promise for treatment of Alzheimer’s, but only within a narrow concentration range and with a very careful approach to determining the dosage levels and the patients for whom it might be helpful.

Lead investigator Dr. Bettina Platt commented, “Clearly, the claim that memantine’s beneficial action is due to the reduction of glutamate signaling needs to be revised. It is highly unlikely that compounds directly targeting glutamate receptors will be successfully introduced into the clinic, since major side effects must be expected.”

That means in the case of memantine, less may be more. It is still a good choice as a treatment for Alzheimer’s disease – very carefully.

More information:

The article, "Memantine acts as a cholinergic stimulant in the mouse hippocampus" by Benjamin D. Drever, William G.L. Anderson, Helena Johnson, Matthew O’Callaghan, Sangwon Seo, Deog-Young Choi, Gernot Riedel, Bettina Platt, appears in the Journal of Alzheimer’s Disease, Volume 12, Issue 4 published by IOS Press.

Contact Astrid Engelen at a.engelen@iospress.nl or market@iospress.nl to obtain the full text of the article or request an interview.

By:

Ann Julian, LCSW-R, MSW, Special to Alzheimer's Weekly

Reviewed for medical accuracy by
Dr. B. Ancselovits, MD, Geriatrician, Alzheimer's Weekly

Sources:

The Journal of Alzheimer's Disease (January 2008)

Copyright:

Copyright © 2008 Alzheimer's Weekly. All rights reserved.