Anti-stutter drug

An anti-stutter drug, that would be invaluable for us all – if we ever dared to dream about it. This report is written in English to enable discussion with our sister organizations abroad, and with the author of the publication, Dr Gerald Maguire. As you may know, he is an American psychiatrist and fellow-stutterer as well. He is devoting most of his time to study his own problem (to help others), and now he has published a paper on the effect of Pagoclone (a Valium like drug) on stuttering. The study carries the provocative title Express: the Examining Pagoclone for persistent sEvelopmental Stuttering Study. We assume that the usage of English will not be a problem for both our professional readers, as well as for our fellow stutterers – especially for those, exposing themselves to the Internet. The most difficult may be the medical and statistical aspects of this study. We will do our best both to give credit to the data (with the inherent complicated wording) as well as to the clarity of the conclusions – which will interest our readers the most. In addition, we will discuss some possibly interesting (but not mentioned) points of this study.

Neuronal activity (required for all our actions and feelings) is mediated by neurotransmitters - think of hormones, but unlike these working only at extremely short distance. In human brain a little substance (100 kD for the more knowing people among us) Gamma-aminobutyric acid (GABA) is an important inhibitor of such neuronal activity. GABA agonists resemble GABA in their binding to the receptor and subsequent inhibitory effect. Various examples of such agonists are , (older sleeping pills) and (more modern anti anxiety drugs). Also GABA receptor antagonistic drugs (i.e. drugs which inhibit the interaction of GABA with their receptors) have been found, and remarkably some of them have been shown to induce stuttering. Benzodiazepines and other drugs have been studied for their ameliorating effect on stuttering (we will come back on that topic in the discussion) and here the effect of Pagoclone (a novel GABA receptor agonist) is described.

The study is well performed in a 2-arm, randomized, double blind way. I.e. all patients (132 adults persistent developmental stutterers) were randomly assigned to 88 patients which were treated with the real drug (Pagoclone) or 44 which were and given a placebo instead in such a way that neither patient nor doctor do know the real situation. In such studies, the code will be broken after a given time, all the data are analyzed and the effect of the drug will be clear. This study was paid by the relevant pharmaceutical industry. That situation is fairly common in such research; clinical research is very expensive (far too expensive for Universities) and here it has not (to our notion) influenced the results. The primary parameters tested included all usual objective and subjective severity scales of stuttering (for the more knowing people under us: SSI-3, SSS, SEV, %SS) as well as secondary parameters, such as SNS (naturalness of speech) and LSAS (psychological aspects). Apart from the pretreatment situation, two or three time points were measured, i.e. (2), 4 and 8 weeks after starting the treatment. After the completion of this double blind part, 119 patients entered an ‘open label’ extension - i.e. both patients and doctors do know that the drug is taken.

Results; in the first part the mean change from pretreatment to on-treatment was measured in all clients on the time points mentioned, resulting in 38 comparative data sets. In almost all situations, (Placebo as well as Pagoclone) these parameters showed improvement. Even for the Placebo group this is not surprising, as even in the absence of an active substance, mere attention tends to improve awareness and control of the situation. Overall the improvement in the Pagoclone group was a little better than in the Placebo group, but almost never (for the more knowing under us) reaching the stringent p= 0.01 level of significance - and that in one of either p values (Median test or Rank ANOVA). In the comparative data set were this criterion was met at the highest level (% SS (syllables stuttered) 4 wks after start treatment) this improvement was 21%. In our discussion, we will come back on this figure – as well as on other significant differences when adopting authors’ more lenient p=0.05 value. In the open label study, the improvement in this criterion (%SS) was kept and even on a higher level to 40% after one year.

Safety; an important aspect of clinical studies is to document undesired side effects. Two side effects stood out: headache, in 7 vs. 13 % of the Placebo and Pagoclone groups respectively; and fatigue in 0 vs. 8% in these groups.

Authors discuss their results as follows and the reviewer will comment on that, duly indicated as such (Rev.:). This seems to be the largest well controlled clinical study on pharmacological treatment of stuttering. An earlier meta-analysis by Bothe et al (2006) critically assessed the relevant literature on the period 1970-2005, and concluded that none of the 31 articles met stringent methodological criteria (Rev.: these are explained in another review on this site: Efficacy of Treatment). In short, all earlier studies suffered from small sample size, short duration of treatment, and no sound reports on the achievement of a SS<5% after pharmacological treatment were seen. Current authors stress that this recent report aimed to improve the sample size and the duration of the study (Rev.: and they seem to have succeeded in that). Although promising, a larger, longer, and dose finding study seems to be required, and according to the authors, such a study is now running. (Rev.: in current study only 2 out of 38 parameters showed statistically sound improvement with one of both p=0.01 values of significance. Authors have adopted however, the more lenient margin of p=0.05, and then 6 out of 38 parameters tested were significantly different in addition. And (as a positive trend was seen throughout) it may very well be possible that this number will increase in a larger study.) Further, the positive effect of the longer treatment (1 yr) was obtained in an open label study, and to be convincing in that point, a double blind approach is urgently required (Rev.: very true). The variability of the data are probably related to the spontaneous waxing and waning of stuttering. (Rev.: this is very much the case so, and it stresses the daunting task to perform any study on whichever efficacy of treatment of stuttering.) Rev. would like to add several points:

Out of 39 datasets, the highest statistical significant difference was seen in the %SS after 4 weeks: authors found here a 21% relative improvement. If we, however, recount these figures from relative percentages to absolute percentages stuttering syllables, the decrease was from a mean 8.5% to 8.3% in the placebo group and to 6.7% in the treated group - anyway not reaching 5% SS. One may seriously doubt, whether a difference of 1.6% SS would be clinically significant, even when it is statistically so. Another statistical point pertains to the Standard Error. Overall, this SE of the mean is (for the large group of Pagoclone treated patients) rather high. That might implicate that in this study not all patients reacted a little, but that one subgroup had reacted stronger and that in another subgroup Pagoclone did not exert any measurable effect. Rev. cannot further comment on this interesting point due to the absence of raw data. It is surprising, however, that authors did not discuss that point: it might implicate that in the future a specific subgroup may benefit from this treatment – and how then to diagnose that subgroup?

The side effects, indeed seem to confound this little positive effect. One may doubt whether one would be willing to pay the price of headache or fatigue, occurring not infrequently during treatment. On the other hand, these side effects may be less when using Pagoclone, than with other anti anxiety drugs. The GABA receptor comprises of various chains and subtypes thereof, and Pagoclone seems to act preferentially with the α2/α3 subtype of the GABA-A receptor chain. As a result of this, Pagoclone would give anti anxiety effects without much sedation or memory-loss - for which the α1 chain would be instrumental. Rev. wonders why current authors have not mentioned that point as a reason to go further with their research.

Interference with neuronal activity using e.g. Pagoclone, would that work in stuttering? Indeed, whatever the originating, maintaining and worsening factors in stuttering may be, there is no feeling without neurons. In view of recent data on stutter genes (already on this site), functional MRI studies of brain in stuttering (upcoming on this site) and a special form of neurogenic stuttering (upcoming as well), the biological factors are crucial – although in view of the plasticity of the brain not inevitable. Stuttering is a very complicated disease, and it may very well worthwhile to attack various components of this vicious circle. In the future, Pagoclone (or similar drugs) might gain their place e.g. in a combined approach with other current therapies. Meanwhile, in our view it is useless (and indeed impossible) to try Pagoclone yourself. Only well controlled studies may be able to help us in our problem. We will hear more about it, and we will publish that also on this site.

Bert Bast