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.

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.

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.

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.

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.

Stuttering and Neurotransmitters

The brain consists of neurons which are basically nerve cells organized to perform specialized functions such as speech. In addition, there are chemicals called neurotransmitters that help to transfer messages in the form of electrical impulses from neuron to neuron.

To understand what happens in the brain when a person stutters as well as how various medications work to reduce stuttering, it is first important to learn about the function of neurons and neurotransmitters.

As shown in the top diagram in the picture at the left, the neuron consists of a cell body, an axon, and numerous branching dendrites at both ends. Messages pass through the brain by traveling through these neuronal structures, beginning as an electrical impulse that is picked up by one of the dendrites of the neuron. Next, the impulse moves through the cell body then travels down the axon. By the time it reaches the end of the axon the electrical impulse is changed to a chemical impulse in the form of a neurotransmitter. These neurotransmitters, released by the axon carry messages from one neuron to another. When the message is picked up by the dendrite of a neighboring neuron, it is changed back to an electrical impulse and the process begins again. Since neurons do not touch each other, the neurotransmitter passes from one neuron to the next through a narrow gap, called a synapse.

Neurotransmitters are specifically shaped so that when they pass from a presynaptic neuron into a synapse, they can chemically bind onto certain sites, called receptors, on a neighboring postsynaptic neuron. Neurotransmitters can fit a number of different receptors, but receptor sites can only receive specific types of neurotransmitters. Upon binding to a receptor site of a neuron, the chemical message of the neurotransmitter may lead to an electrical impulse that continues on its way toward the next neuron, or it may stop where it is. In either case the neurotransmitter releases from the receptor site and floats back into the synapse. It is then removed from the synapse in one of two ways. The neurotransmitter may be broken down by a chemical called monoamine oxidase, or it may be taken back in by the presynaptic neuron that originally released it. This last process is called neurotransmitter reuptake.

The current hypothesis regarding stuttering is that it is caused by excessive dopaminergic activity in the motor neuron section of the brain. The bottom diagram of the picture above shows the detail of a neuronal synapse. The neurotransmitter, dopamine, is released from the dendrite of a presynaptic neuron at the left of the diagram and binds to a dendrite of a postsynaptic neuron (shown as a "tail") in the middle of the diagram.  Dopamine is an excitatory neurotransmitter.  On the right is another dendrite which releases GABA that happens to be an inhibiting neurotransmitter. What this means is that when GABA binds to the postsynaptic neuron, it inhibits or blocks the action of dopamine and hence modulates its excitatory action. So if stuttering is caused by excessive dopaminergic activity, we have several courses of action. The first is to directly block dopaminergic activity in various ways and the second is to increase GABAergic activity by various means.

Dopamine is an agonist, which is a chemical that binds to a receptor of a neuron and triggers a response by that neuron. In addition to dopamine, there are other neurotransmitters in the brain that act as agonists.  Also, drugs introduced exogenously into the brain may act as agonists.  On the other hand, GABA is an antagonist in that it blocks the action of the agonist. And similarly to an agonist, there are other neurotransmitters that are antagonists and drugs may act as antagonists.

In the next post we will discuss drugs that may affect dopaminergic activity in different ways.

Stuttering and Dopamine

The current hypothesis regarding the physiological cause of stuttering is that there is excessive dopaminergic activity in the motor neuron portion of the brain. We emphasize that this is a hypothesis which does not yet have the status of a highly tested theory. Although brain imaging studies have shown that people who stutter exhibit above average motor neuron dopaminergic activity, this observation is a correlation rather than a cause/effect chain. The administration of certain atypical antipsychotic drugs which are known to reduce dopaminergic activity also reduce the level of disfluency and this provides some support for a cause/effect relationship. But additional evidence is needed to further support the hypothesis.

Stuttering begins to manifest itself in preschool children and some children outgrow this fluency problem. Is excessive dopaminergic activity present in the brains of these children? Is there any difference in the dopaminergic activity of children who outgrow their stuttering compared to those who do not? Are there any environmental influences that govern the different paths that children take toward fluency that may influence dopaminergic activity?

In addition, we may inquire as to whether or not any of the psychologically based speech therapies affect dopamine levels. If the effects of these therapies are temporary, can changes in dopamine activity be observed? Also, to what extent does the administration of placebos affect dopamine levels? Do illegal drugs, most of which accentuate dopamine activity, have a negative effect on all or most stutterers?

We also want to get at the question as to what causes the physiological structure of the brain that results in excessive dopaminergic activity. Is it nature or nurture? Are there specific genes that can unambiguously be associated with stuttering? Or does nurture in the way of the environment play a major role in the development of disfluency? If the problem is principally with genes, is some sort of gene therapy possible for the treatment of this problem?

These are some of the questions that need to be answered before the dopamine hypothesis can be accepted as a theory.

Parkinson's Disease, Dopamine, and Stuttering

In the previous blog entry, we discussed the possibility of a nocebo-like effect having an influence on stuttering. Basically, the context in which an individual finds himself can have a negative effect on his fluency. This is a result of a conditioning mechanism whereby a specific context is associated with greater disfluency.

Victims of Parkinson's disease have a deficit of dopamine activity in the same area of the brain in which stutterers have an overabundance. And an interesting observation is that Parkinsonism patients receiving a placebo showed a substantial increase of dopamine activity in this part of the brain according to brain imaging results. So we can wonder if, similarly, the nocebo-like effect of context on stuttering might also increase the level of dopamine activity in the brains of stutterers, thus negatively affecting their fluency.

The diagram discussed in the blog entry entitled "Mind/Body Problem" is repeated here with the specific labels related to stuttering replacing the generalized labels of the previous diagram.  Note that the "Anxiety" label was replaced with the "Mind" label since anxiety can be viewed as a state of the mind.  So basically, stuttering affects the mind (i.e., causes anxiety) which in turn affects stuttering.  In addition, the context (e.g., speaking before an audience), through conditioning, further affects the mind and the subsequent lack of fluency.
However, given the possible dopamine connection discussed above, we can modify the diagram as follows:

 Note that the directed line now goes from "Mind" to "Excessive Dopamine Activity) instead of going to the "Stuttering" node, reflecting the possibility that context, acting as a nocebo, will directly affect dopamine activity which in turn affects fluency. This representation of the mechanism for stuttering has the advantage of following the law of parsimony in explaining stuttering.

Stuttering, Placebos, and Nocebos

A placebo is a sham medical intervention that may produce a therapeutic effect in a patient. For example, an inert pill can be administered with the suggestion that it may improve the patient's condition. The result, called the placebo effect, is an excellent example of how the mind can affect a physiological reaction and the impact of positive expectations on biological outcomes.

There are also placebo-like effects whereby no physical placebo is administered, the effect being due to the influence of a specific context on the patient's mind (e.g. verbal suggestions of improvement). Regardless of the exact nature of the placebo, expectation of a future outcome is a principal mechanism for the placebo effect.

Also, a conditioned neutral stimulus (e.g., the color of a sham pill) can become a placebo if it is repeatedly associated with an unconditioned stimulus (e.g., the drug inside a real pill). Therefore, a patient who is initially given a real pill and is subsequently switched to a sham pill of the same shape and color may continue to show therapeutic effects. Conditioning leads to the expectation that one event will follow another event on the basis of the information that the conditioned stimulus provides about the unconditioned stimulus. This is called the conditioned response model.

On the other hand, nocebos are essentially the opposite of placebos in that nocebos may lead to negative pathological effects. Beliefs and expectations may sicken or kill, as in the extreme case of voodoo deaths. Negative expectation inducing events or procedures may lead to symptom worsening. The fear/avoidance model of pain can be viewed as a kind of noceba-like effect, whereby the fear of pain may lead to the worsening of pain. As with placebos, we might also expect that nocebos could exhibit a conditioned response mechanism. And this is where nocebos may play a role in stuttering.

A stutterer may have had embarrassing experiences in a given context with his speech (e.g., speaking in front of an audience); this is the conditioned stimulus. Since this stimulus is repeatedly associated with the stuttering, conditioning will lead to the expectation that stuttering will follow standing before an audience. The noceba effect offers a rationale for the diagram shown in the blog posting entitled "Stuttering, the Mind, the Body," in that a context (e.g., public speaking) can result in a worsening of one's fluency.

More on Mind/Body Connection

Disfluency is a combination of brain disfunction and mind involvement. The usual standard for judging stuttering severity is the number of disfluencies experienced over a given tIme period when reading, for example, a given amount of text. But the severity of stuttering gives no indication of the extent of brain involvement in the episode given that the mind and the context also come into play. In the ideal, we would like to rank the brain involvement on a scale from 1 to 10, where 1 is the least severe and 10 is the most severe. Similarly, the mind involvement can also be ranked on a 1 to 10 scale. So the most severe episode of stuttering would have a score of 20, while the least severe would be scored a 2. An individual may have intense brain involvement with a score of 10, yet not be very reactive and have a mind involvement score of 1, for a total of 11. Another person may have a mild brain involvement with a score of 1, yet be very reactive with a mind involvement score of 10, again for a total of 11. In both cases, the severity of stuttering may be the same, but the underlying causes would be different. And each of these cases may respond differently to treatment. For example, the person with greater mind involvement might respond better to psychologically based therapies while those with substantial brain involvement would show better improvement with drug therapies.

Unfortunately, it would be very difficult to disentangle the brain involvement from the mind involvement on a priori grounds. A clinician might be able to infer the relative amounts of involvement only after observing treatment results.

Stuttering, the Mind, and the Body

There are many ailments that start as a problem with some part of the body but are made worse when the mind comes into play. Knee or back pain may have its roots in some physical problem with one's bones, ligaments, or tendons and this may cause some discomfort or pain. But in some individuals, the mind comes into play and this discomfort or pain becomes intensified. Another example is erectile disfunction, which may initially have some physiological roots, start out as relatively mild, but through repeated embarrassing failures end up as a more intense problem. This phenomenon is called the mind/body connection.


It turns out that stuttering has a strong mind/body connection for most people with this problem. It is currently believed that in the great majority of cases stuttering starts in a preschool child because of a malfunction in the motor neuron section of the brain. At this point in time the child is relatively unaware of the problem, but by the time he reaches school age, parents reacting negatively and teasing schoolmates make him acutely aware. What happens at this point is that the mind comes into play  resulting in secondary stuttering characteristics such as blocking, twitching, etc. So the initial fluency problem is intensified by the action of the mind. This mind/body connection (the body part involved being the brain) can be depicted in the diagram below:

Starting from the left, some root cause--in the case of stuttering an abnormality in the brain--leads to a physical problem, namely stuttering.  This physical problem results, at some point, in anxiety which may vary depending upon the context in which the stutterer finds himself (e.g., speaking before an audience).  This anxiety then feeds back into the physical problem, perhaps making the stuttering worse.  So the physical problem is in some sense the product of a body problem (in this case the brain) and a mind problem (in this case the awareness and the anxiety associated with stuttering.

INTRODUCTION

This blog is dedicated  to exploring stuttering and its connection to both the mind and the body.  Future posts will provide information about the current understanding of the causes of stuttering, e the role of the brain in stuttering, as well as the role of the mind.  The mind is distinguished from the brain in that the brain is the physical mass that exists in your skull, while the mind is a manifestation of the brain (e.g., consciousness and self-awareness).  In addition, future posts will deal with the role of drugs in treating stuttering, drug trials, and their interpretation.

Many of the readers of this blog had high hopes for the recent pagoclone drug trials, but recently the pharmaceutical company, Indevus, announced the termination of these trials.  There could be many reasons for this termination, one of which is that the drug did not perform statistically better than a placebo (i.e., a sugar pill).  Another possibility is that the drug did not live up to other "success criteria" set up for it.  For example, a user of the drug may develop a tolerance for a given dosage (this is common for tranquilizers) and that dosage may subsequently become ineffective for improving fluency.

At any rate, a number of test subjects in the pagoclone trials have reported extended fluency improvements  while on pagaclone and decreased fluency while on the placebos.  So we can await future announcements from the drug company as to the reasons that the trials have stopped.

So tune in for future posts on this blog.  I'm sure that you will find them to be educational and informative.