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.

Wednesday, September 22, 2010

Grants for Hollins Institute

In the September 21st edition of the Wall Street Journal (the New York section, not available to all readers), an article appeared about Sander Flaum. He is a marketing consultant and adjunct professor at Fordham University. Mr. Flaum stuttered until the age of 30, at which point he enrolled in a speech therapy program at the Hollins Communications Research Institute in Roanoke, Virginia. He claims to have gotten his fluency problem under control, but still needs to practice daily.


Through the Rose Flaum Foundation, he is offering grants of up to $4000 to those in need who wish to enroll in the Hollins program, which is several weeks long. The Foundation is funding the program to the tune of $100,000 per year, so there should be over 25 grants offered each year. No contact information was given in the article.

Thursday, September 16, 2010

Atypical Antipsychotic Drugs and Stuttering

Stuttering may be caused by excessive dopaminergic activity in the motor neuron section of the brain. More specifically, it is the dopaminergic activity in the nigrostriatal pathway involved in motor function that has been implicated in stuttering. On the other hand, excessive dopaminergic activity in the mesolimbic pathway involved with emotion and memory has been linked to schizophrenia. Since individuals who stutter generally do not exhibit schizophrenic tendencies, the levels of dopaminergic activity are obviously unique to different parts of the brain.


In several of the previous posts, we indicated that one way to inhibit the activity of dopamine is to enhance GABAergic activity, which can be accomplished with BZs or pagoclone. Although the claim has been made that stuttering is linked to too much dopaminergic activity, the problem may be that there is too little GABAergic activity in the relevant sections of the brain. There are other drugs that may enhance GABAergic activity and we will discuss these in future posts.

But in this post, we want to discuss more direct approaches to limiting dopaminergic activity, namely through a class of drugs called atypical antipsychotics. These drugs, which include Risperidone, Zyprexa and Abilify, were designed to treat conditions such as bipolar disorder, schizophrenia, mania, and delusional disorder. More recently, they have been used off-label to treat stuttering.

These drugs work directly in that they block dopamine receptors (namely the D2 receptors) on neurons so that dopamine that is present in the synapses cannot itself bind to these receptors. In this way, the activity of dopamine is reduced.

This variety of drug therapy has been strongly promoted by Dr. Gerald Maguire, the director of the Kirkup Center for the Medical Treatment of Stuttering at the University of California, Irvine. For those who are interested, the web-site of the Center is:

                            http://www.healthcare.uci.edu/psych/stuttering/

Unfortunately, atypical antipsychotics may have some side effects such as sedation, dyskinesia (involuntary muscle twitching) and may lead to weight gain and potentially diabetes. Major research is currently being conducted to develop a new generation of atypical antipsychotics exhibiting reduced drug side effects.

Wednesday, September 8, 2010

Pagoclone, GABA, and Stuttering

Pagoclone had previously been tested as a drug to relieve anxiety. One of the participants in the study who stuttered noted that when taking the drug he experienced greater fluency. So it was decided that larger scale trials would be conducted to test the efficacy of pagoclone as an anti-stuttering medication.

Pagoclone is a member of the class of drugs called cyclopyrrolones. However, it acts like a BZ in that it binds to BZ receptor sites on neurons, the difference being that it binds only to some of the subtypes within a BZ binding site, specifically to the alpha-2 and alpha-3 subtypes. Hence, it does not have some of the negative effects of BZs such as causing sleepiness and, it is claimed, less tendency to induce physical dependency, addiction, and tolerance. In any case, pagoclone facilitates the binding of GABA to post-synaptic neurons which in turn inhibits the action of dopamine, implicated in stuttering.

Pagoclone had been in phase 3 drug testing by Endo Pharmaceuticals, but the testing program was abruptly halted recently. No explanation to this date has been given. A number of individuals partaking in the program have anecdotally reported positive results. In most cases disfluency was substantially reduced but not completely eliminated. It would seem that the humane move by Endo would be to test the drug for safety, release it to the public, and let the market determine its fate.

Many individuals who stutter and have not been part of the testing program had been eagerly waiting for pagoclone to reach the market. Many are curious as to whether or not this drug would improve their fluency. Perhaps this question might be answered indirectly by trying a BZ instead. Since the action of the two drugs is basically the same, the extent of fluency improvement using a BZ might give an indication of the potential efficacy of pagoclone for any given individual.

Saturday, September 4, 2010

Stuttering, GABA, and Benzodiazepines

In the last post, we discussed the neurochemistry of the brain and its effect on stuttering. In particular, the neurotransmitter GABA acts as an inhibitor and reduces the effect of the neurotransmitter, dopamine, which has been implicated in stuttering.

In this post, we discuss various drugs that may enhance the action of GABA. There are basically three mechanisms to accomplish this:

      • The amount of GABA in the synapse between two neurons may be enhanced
      • The reuptake of GABA into the presynaptic neuron may be inhibited, thus
         maintaining the level of GABA in the synapse
      • The binding of GABA onto the post-synaptic neuron may be encouraged.

Benzodiazepines (BZs) are drugs that encourage the binding of GABA onto post-synaptic reeptors. The mechanism involved is that BZs themselves bind to BZ receptors on the neuron. BZ and GABA receptors exist together in an interactive complex. In effect, the binding of BZ facilitates the binding of whatever GABA is in the synapse (one of the puzzles of neurology is that there are BZ binding sites on neurons but BZ is not a naturally occurring chemical in the brain). And when GABA binds to a neuron, as shown in the diagram of the previous post, it inhibits the action of dopamine in the motor neuron section of the brain, hence improving fluency. Examples of BZ drugs are Valium, Ativan, and Xanax.

While BZs may reduce the incidence of stuttering through the mechanism cited above, they also have side effects such as the reduction of anxiety and sleep inducing properties. While the former may be beneficial for a stutterer since stuttering is partially a mind problem (see the post on the Mind-Body Problem), the later property is a liability. In addition, with continuous use a dependence and tolerance may be built up for the drug. So BZs should be used selectively and sporadically for situations when the individual expects to be in an anxiety producing situation such as speaking before an audience or engaging in a job interview. In such situations, the effect of the BZ should be to improve fluency and not have much of a sleep inducing effect because of the high initial state of anxiety.

Some stutterers using BZs have also reported that it heightens the level of their articulateness. Thoughts, ideas, and words seem to flow more smoothly. This phenomenon may be explained in two ways. First, greater fluency enables one's speech to keep up with one's thoughts, so there is a closer temporal match between thoughts and speech. Secondly, a study conducted in a nursing home indicated that patients given low dosages of a BZ became more lucid in that they were able to communicate in a more coherent manner. The speculation was that administration of the drug reduces "brain noise." So "brain noise" because of excessive dopaminergic activity may be what stutterers have in the motor neuron section of the brain as well as elsewhere in the brain, which may adversely affect articulateness as well as fluency.

In the next post, we will discuss pagoclone and stuttering.