Expert Interview

David Charles, MD, and Thomas Davis, MD, on updates on levodopa-induced dyskinesia treatment and research


Take epilepsy, for example. In operative candidates, surgery is often more beneficial when applied earlier. There's solid data to support that adding on multiple anti-epileptics medications is not always helpful. Continuing to add or change medications can actually diminish returns, particularly in a person who could receive benefit from surgery for epilepsy.

I get the sense that the same may be true for dyskinesia. In clinical practice, we often receive DBS referrals when a patient's community-based physician has tried various medications and combination therapies until the point that the patient and the physician have become totally frustrated. By the time they are referred, the patient may benefit from DBS, but not nearly as well and as for long as they could have if they had received it earlier. We as physicians have to be mindful that while we have these increasing number of options—which is a good thing for both patients and physicians—that we don't continue to use them to the point that it takes away the option of more advanced therapies for appropriate candidates.

Metabotropic glutamate (mGlu) receptors have been receiving attention as potential therapeutic targets for LID. How do these compare with other receptors such as N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA)?

Dr. Thomas Davis: NMDA and AMPA are traditional ionotropic receptors, meaning that they are ligand gated, that they are almost exclusively excitatory, and that they generally have to do with the flow of potassium.

mGlu receptors are protein coupled receptors. They have more elaborate action and may be either excitatory or inhibitory. Though mGlu, NMDA, and AMPA are completely different, they are all activated by glutamate. Pharmacologically utilizing the mGlu receptors is a relatively new and novel idea. Specifically, mGlu-5 receptors have received the most attention as potentially having an anti-parkinsonian effect and possibly dampening dyskinesia. The mGlu-5 receptors are an attractive target because they are concentrated in the striatum, as opposed to other glutamatergic receptors that are more diffusely located. It was felt that mGlu-5 modulators would be more specific and have less of the potential adverse effects of other glutamates. Most drugs that we think of affecting glutamate, like amantadine and memantine (used for Alzheimer's disease), have some NMDA antagonist effect, but this is relatively mild.


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