Sunday, September 26, 2010

Beyond Pagoclone, Part 1

Amazingly, for many decades articles published in the medical literature indicated that BZs had no impact on the fluency of stutterers. More recently with the advent of the dopamine hypothesis of stuttering, medical researchers as well as individuals using BZs off-label have reported its positive effects on fluency. And, of course, with the recent testing of pagoclone, which acts much like a BZ in facilitating GABA binding and consequently blocking dopamine activity, the role of the GABAergic system as it affects fluency has come to the fore.

In fact, as was pointed out in a recent post (see "Atypical Antipsychotic Drugs and Stuttering"), it may be a dearth of GABAergic activity in the motor neuron section of the brain that leads to reduced fluency rather than excessive levels of dopamine or an overabundance of dopaminergic receptors. If this were the case, we would then have a GABAergic hypothesis of stuttering.

With this in mind, we look beyond BZs and pagoclone in this post to medications that may affect GABAergic activity by other means. In a previous post entitled "Stuttering, GABA, and Benzodiazepines", we pointed out that GABAergic activity can be enhanced in several ways. First, we can facilitate its uptake to post-synaptic neurons by using, for example BZs or pagoclone. Second, we can increase the amount of GABA or GABA analogues in the synapses. And, thirdly, we can reduce its re-uptake into the pre-synaptic neurons, in effect maintaining higher GABA levels in the synapses. In this post we focus on the last two approaches to affect GABAergic activity.

The classes of drugs we discussed previously fall loosely into the anti-anxiety (e.g., BZs) and the anti-psychotic (e.g., zyprexa) categories. The drugs discussed here fall generally into the anti-epileptic category. The following are just a representative sampling of the scores of drugs in this category.

Vigabatrin increases the level of GABA in the synapses. It does so by inhibiting the action of the enzyme, GABA-transaminase (GABA-T), which is responsible for the elimination of GABA. Moreover, when GABA-T reacts with GABA, it ultimately leads to the production of succinic acid and succinic acid further inhibits the production of GABA. Vigabatrin has been implicated in causing visual field defects, specifically affecting the outer area of the retina.

Depakote has no effect on GABA-T but instead reduces the level of succinic acid itself so that the production of GABA is not inhibited. A potential drawback of Depakote is that it may adversely affect the pancreas.

Phenibut acts as a GABA analogue binding primarily at GABA-B receptors but to some extent at GABA-A receptors. This drug has been widely used in Russia as an anti-anxiety medication, to treat insomnia, as an anticonvulsant, and as a treatment for stuttering. It has been available over-the-counter in the United States. There is some risk of drug dependency and withdrawal symptoms when usage of this drug is discontinued.

Other drugs that act as GABA analogues (also called GABA-mimetics) include Baclofen, Progabide, Fengabine, and Tolgabide.

Gabapentin increases GABA primarily by enhancing the release of GABA from glia, which are non-neuronal cells within the brain. The structure of gabapentin is similar to that of GABA but it does not act directly on GABA receptors. When administered over an extended period, there was no evidence of tolerance or physical dependence after abrupt termination.

Tiagabine, a GABA reuptake inhibitor, blocks the activity of GABA by binding onto GABA receptor sites of presynaptic neurons, which then prevents the reuptake of GABA into these presynaptic neurons. Thus, more GABA will be present in the synapses and available for binding onto post-synaptic neurons.

In summary, since the track record of the medical establishment in identifying drugs that may improve fluency has been extremely poor and research on candidate drugs is moving at a snail's pace, the purpose of this post is to stimulate thinking in this area. The most likely classes of existing drugs that may be possible fluency enhancing candidates are those associated with relieving anxiety, alleviating psychosis, or controlling epilepsy/convulsions.

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