Friday, October 22, 2010

Proposal for Beyond Pagoclone Drug Trials

We have argued in previous posts that there may be several potential etiologies (causes) of stuttering--namely excessive dopaminergic activity, insufficient levels of GABA, or inadequate neurosteroid production. Moreover, these chemical imbalances in the brain may stem from a myriad of problems. For example, excessive dopaminergic activity may be due to the production of too much dopamine, or too large a density of dopamine receptors on post-synaptic neurons, or insufficient dopamine reuptake by pre-synaptic neurons. Similarly, in our discussion of GABAergic drugs we have seen that the level of GABA depends on a number of factors as well.

It is reasonable, therefore, to speculate that stutterers might fall into subgroups based on the potentially different underlying root causes of their disfluency. If this were the case, then we could not expect that all individuals would respond the same to any specific drug therapy. And this observation has implications for the testing of the impact of drugs on fluency.

Given that a number of different drugs have been identified that target different pathways leading to excessive dopaminergic activity, it is reasonable to propose that these drugs be put through clinical trials to test their efficacy on fluency. Since the drugs are currently on the market and used for other purposes, presumably their safety already has been established to the satisfaction of the relevant government agencies. Thus, phase 3 trials testing for safety may not be required for these drugs.

One difficulty with conventional trials is that they basically take all comers. Many participants may not benefit from a specific drug treatment and those who do not respond may cause the drug to fail even though a significant minority might benefit.

A new model, called "adaptive design," for drug trials has been applied to the treatment of breast cancer. It focuses on leaner faster trials involving simultaneous testing of multiple drugs that enroll patients with a higher probability of responding to a specific treatment. And, unlike conventional trials in which results are not examined until the end, data is examined as the trial progresses. What is learned in the early going determines which drugs are administered to specific trial participants later in the study.

This model can be adapted to the testing of drugs that may affect fluency. Unlike drugs for breast cancer where a cure is sought, fluency enhancing drugs are a palliative rather than a cure. Thus, it may even be possible to eliminate a standalone control group in such a design by cycling trial participants through periods where the drug being tested is replaced by a placebo and observing the effect on both fluency using standard methods and on dopaminergic activity via brain scans. In addition, given the existing theoretical understanding of the action of a drug, the classification of trial participants may be further refined according to their specific etiologies.

Finally, since the clinical trials would involve existing drugs from a number of commercial pharmaceutical companies, it would be appropriate that the trials be conducted by a government organization (such as the NIH), a clinical trials unit in the academic sector, or a contract research organization not affiliated with any pharmaceutical company. In this way, we could enhance the level of objectivity of any such study.

Saturday, October 16, 2010

Beyond Pagoclone, Part 3

In this post we look at a couple of alternative over-the-counter supplements that have been tried as fluency enhancers. In the previous posts, all of the alternative drugs discussed require a doctor's prescription except for Phenibut.

Some stutterers have reported mildly improved fluency when taking an over-the-counter supplement 5-HTP (see blog). Since 5-HTP is claimed to be a serotonin activity enhancer, the question arises as to how this may come about. The answer may Iie in some research conducted by a group of Stanford University medical researchers (see Andrews et al, Journal of Neurochemistry, 1978, vol. 30, pp. 465-470; also see They claim that 5-HTP may be a dopamine depletor based on their studies with rats. Thus, reducing the levels of dopamine according to the dopamine hypothesis of stuttering should improve fluency. Whether or not 5-HTP has long lasting effects or has only a transient impact is an open question. To my knowledge, no controlled double blind trials have been conducted to determine 5-HTP's effect on fluency.

Vitamin B-6 has also been tried as a fluency enhancer (see blog cited above). The idea here is that vitamin B-6 is involved in the production of GABA, which inhibits the action of dopamine. But the situation is a bit more complicated than that as we see in the somewhat simplified diagram below.

Indeed, B-6, along with Glutamate and GAD (glutamic acid decarboxylase), is involved in the GABA synthesis process (denoted by the green directed lines). And GABA inhibits the action of dopamine as shown by the red directed line.  But note also that B-6 reacts with GABA along with GABA-T (GABA-transaminase) to produce succinic acid which is involved in the negative feedback inhibition of GAD (again denoted by the red directed line). In addition, we also see from the Figure that B-6, along with Dopa is involved in the production of dopamine. So B-6 has a positive effect on the production of GABA, but also a negative effect on GABA levels because of its reaction with GABA and GABA-T (producing succinic acid), and an additional negative effect by way of being involved in the synthesis of dopamine. Obviously vitamin B-6 plays a delicate balancing act in maintaining an equilibrium among different neurotransmitters except perhaps in the brains of stutterers. Based on the above discussion, it is very difficult to determine what the net effect of taking vitamin B-6 might be on the fluency of any particular individual.

Friday, October 8, 2010

Beyond Pagoclone, Part 2

This post discusses two additional drugs that may act to improve fluency.

Pregabalin, marketed by Pfizer under the trade name Lyrica, is claimed to be a more potent successor to gabapentin. Pregabalin increases GABA levels by enhancing GAD (glutamic acid decarboxylase) activity. GAD is an enzyme that converts the excitatory neurotransmitter glutamate into the inhibitory neurotransmitter GABA. By this action, pregabalin also decreases the level glutamate and, in addition, decreases the excitatory neurotransmitter norepinephrine.

Pregabalin's therapeutic effect appears after about a week of use and is similar in effectiveness to BZs, but it is claimed that pregabalin produces more consistent therapeutic effects for anxiety symptoms. In addition, unlike BZs, it appears that pregabalin is effective over the long term without the development of tolerance, does not disrupt sleep patterns, and leads to less severe cognitive and psychomotor impairment. Its lower potential for abuse and dependence makes it preferable over BZs.

In addition to binding sites for GABA and BZs, GABA receptors also contain binding sites for various neurosteroids, which are produced naturally in the brain. . The transfer of cholesterol into glial cells is involved in the synthesis of naturally occurring neurosteroids such as allopregnenolone and tetrahydrodeoxycorticosterone. These neurosteroids, much like BZs, enhance the activity of GABA

An excitatory neurotransmitter such as dopamine acts as a gas pedal to use an automotive analogy, while GABA acts as a brake pedal. The level of neurosteroids, which act as a brake fluid, control how strongly the brakes (i.e., GABA) are actually applied. So increasing certain neurosteroid levels will increase GABA function, thus reducing dopamine function. In effect, these neurosteroids bind to and modulate the behavior of neuronal GABA receptors.

Neurosteroid drugs such as ganaxolone, an analog of allopregnanolone, which is a positive modulator of GABA-A receptors, may have advantages over other GABA-A receptor modulators, notably BZs, in that tolerance does not appear to occur with extended use.

In a previous post, we discussed the dopamine overabundance hypothesis of stuttering, which assumes excessive dopaminergic activity either because of an overabundance of dopamine receptors in the motor neuron section of the brain or because of excessive amounts of the excitatory neurotransmitter dopamine in this brain region. But if neither of these conditions is present, the problem might be that there is insufficient GABAergic activity, which would inhibit the dopaminergic activity. This leads us to a GABA insufficiency hypothesis of stuttering. In view of the discussion regarding neurosteroids in this post, we can posit a third hypothesis of stuttering--namely the neurosteroid insufficiency hypothesis of stuttering. Insufficiency of certain neurosteroids may lead to a weak GABAergic response which, in turn, results in an overly active dopamine system.

Monday, October 4, 2010

Proposal for Pagoclone Drug Trials

It can take a billion dollars, thousands of patients, and more than a decade to gather evidence to approve a new drug. A big part of the problem with conventional trials is that they essentially take all comers. In some cases researchers might know that some participants may not benefit from the treatment. Those who do not respond can cause a drug to fail even though a significant minority of patients could benefit.

Unless something different is done, we may have to wait a very long time for a fluency improving drug. Perhaps the problem lies in the current policy that it is necessary to absolutely, positively prove (e.g., to the 99.9999% level of certainty) the efficacy of the drug before releasing it to the public. For any potentially fluency improving drug such as pagoclone, we might expect all sorts of objections to be raised when the results of any clinical trials are published. For example, although improvement may have been observed in a clinical setting, will this improvement be observed post-clinically after a long period of time? Is the disfluency counting method reliable? Etc., etc.

The most vociferous critics of fluency drug testing (e.g., The Stuttering Brain blog; Roger Ingham, Journal of Clinical Psychopharmacology, October, 2010) rely heavily on the placebo argument to bolster their beliefs and prejudices--namely that individuals respond favorably to a particular drug not because of its therapeutic efficacy but rather through a placebo effect. And, according to them, this effect might be short lived. Since stuttering is basically a mind-body problem, and the mind plays a very important role in the severity of the disfluency, it is no wonder that it is very difficult to disentangle any real therapeutic effects from placebo effects. In addition, naturally occurring fluctuations in the levels of neurotransmitters may further obfuscate clinical trials. Listening to these critics may result in paralysis through analysis with regard to the search for fluency enhancing drugs.

So my proposal is that for such a drug like pagoclone, why not release the drug on the market AFTER testing for safety? In this way, a population larger than that of any clinical trial could try the drug and decide for themselves as to its efficacy. In essence, it will be the market that decides its success or failure. For some, the drug may prove to be a boon to their fluency, while for others the effect may wear off after time. If the effect does wear off, it does not necessarily imply a placebo effect. An alternative explanation might be that tolerance to the drug may have been built up. In which case, for these people, the drug would better be used in a punctuated fashion with periods of use separated by periods of no use. And, of course, there may be a group for whom the drug does not work at all.

The final concern would be the cost of the drug to the consumer if it were released in this fashion. In the ideal, the cost of a drug that has less than strongly proven efficacy should be less, since the cost of excessive testing was substantially reduced. However, given that the capitalistic system is what it is, perhaps the government should step in and regulate not only the release of such drugs, but also their cost, much as governments often regulate the prices that utilities charge for their products or services.