IFA conference: RCTs

I have just started writing the article for my upcoming IFA presentation: "Lies, damned lies, and random control trials". The title might be a bit strong, but in today's world you need to get out strong message to get people's attention! The presentation is about the use of random control trials (RCTs) in stuttering. In the last year, two main treatment studies have used RCTs: the Pagoclone and the Lidcombe study. I want to show that RCTs cannot just be blindly applied to study the efficacy of treatment studies. This is especially the case for early-childhood dysfluencies.

Here is what I say. This is typically the result of months long subconscious brain storming and discussions with others.

First, I will explain what an RCT is. I have to admit that I have never been formally trained to know what an RCT is, so I have to make it up and looking at a few sources. What I understand as the standard form of RCT is the following: You have a group of people affected by a condition (high blood pressure, AIDS, worm infection, etc). You have a medication which you administer in form of a pill, and you want to see whether the treatment is effective. You split the group into two subgroups: a control group, and the treatment group. You have to do this in such a way as to create the same type of group; for example you select them randomly, and possibly control for the age or gender in each group. You give a pill to both groups, but only the treatment group receives the true medication and the control group a non-effective substance. The level of the condition is measured in both group before and after the test phase.

... I need to drive to the airport now .... still havent written the talk... i'll do it on my laptop... I will fly to Estonia first visiting a friend and doing a day visit to Russia! Then I am going to Dublin for IFA.

Abstracts from Nijmengen Conference

The abstracts of the 2006 Nijmengen conference is out: look on their website under Abstracts, and you will get a pdf file. Thx to Oren for this information! The conference is by far the most scientific one that also deals with stuttering.

Working on my IFA contributions

I am currently working on my contributions to the IFA proceedings. The deadline is on Friday, but sending it by Monday morning if enough. Unfortunately, I haven't started with the articles nor the presentations yet! And rumors go that others haven't done much more either. This is a typical occurrence for conferences. In many cases, deadlines are postponed by a week or two, and I would be surprised if the same happens here.

So what am I going to talk about? The first talk is rather low-key and non-controversial. I am going to give a workshop with "How should we use the Internet to help researchers and do meta-analysis?". I am hoping that people are discussing ways to utilise the Internet for research on stuttering. As a warm-up, I will give a quick presentation on different ways on how this could be done, and on what the obstacles are in my opinion. And then hopefully the participants will "take over" and a lively discussion will start. Here is a list of Internet utilities that I find useful:

- Pub Medline: Internet archive of all published articles on stuttering
- Messenger and VoIP: Chatting and talking to other researchers for free (I have done this extensively with Per Alm, Roland Pauli, and Oren Civier)
- Email: goes much faster than writing letters. Yaruss & Onslow debate (but this one is old by now! :-)
- Pdf / Word Files: you can easily send your research article to someone. (I often ask researcher to send me their article).
- Mailing List:
- List Archive: like Judy Kuster
- Blog: THE STUTTERING BRAIN of course, always the latest on stuttering (big readership after Pagaclone story broke=
- Replis in Blogs: Ingham.
- Online conferences:
- Wikipedia entry
- Open articles & Replies:

Some issues:

- researchers have no time.
- too many sources.
- secrecy dominates.
- old generation.
- no real scientific debate: more teaching of others
- too much information.
- difficult to judge quality of information
- etc

So I will make 4-5 slides for this workshop, and write 1-2 pages. That's it. The other article will be hard-core science. I want to make people aware that you cannot just apply the standard random control trials framework for stuttering. I have done a few statistical simulations, and show that for example the Lidcombe results are not as clear as they think.

More tomorrow.

Travel companion(s) after IFA?

I will be at the IFA conference in Dublin in two weeks' time.

The conference ends on Friday midday, I think. My flight goes back on Monday evening from Dublin. So I have from Friday midday to Monday evening to travel around Ireland. But I havent planned anything yet. I might rent a car.

If you are also at IFA and have some extra days, pls let me know and we can join forces! Preferences are obviously given to girls, people at my age (or younger :-), and stutterers! :-)

My email is tom DOT weidig AT physics DOT org

Auditory system: cause or necessary condition only?

I have spoken about the findings of several research articles that claim an abnormality (in activation or anatomy) in the auditory system, and its consequences: see here. I said that it dont believe that "bad hearing" is causing stuttering.

While cycling up a long hill (trying to imitate the Tour de France), I suddenly came up with a way that might explain lower activation in auditory regions. Here is the line of arguments:
1) People with PDS at birth have no different hearing capabilities (or potential for) than the average population.
2) Learning to speak effectively involves fine-tuning your neural networks to produce speech, and this is only possible with feedback from your auditory system. You need to hear to be able to fine-tune your speaking networks. That's why deaf kids cannot learn to speak properly (except if they get a Cochlane implant).
3) Some kids have a better auditory system than others, but they all manage to learn to speak.
4) Now, I assume that dysfluent kids have an inherent weakness / abnormality (genetics or neurological incident), and the fine-tuning becomes more difficult.
5) Only the kids that have abnormally good hearing are able to do the fine-tuning and recover. The kids with average and lower activation do not, even though had they not had the weakness / abnormality they would have.
6) So looking at dysfluent kids you will find average hearing capabilities (thinking everything is fine). But in adults with PDS you will see an on average lower activation of auditory system.
7) One can even argue that only a temporary delay in the development of the auditory system around age 3-5 will hinder fine-tuning. So you wont see a statistical signal either for all dysfluent kids or for stuttering kids after age 5.


This is only brainstorming. But this scenario shows well that something might not be a cause of stuttering (the weakness / abnormality is), but a necessary condition for it to happen.

Timeline of remission?

I am looking for the time line of remission (i.e. the recovery from (early childhood) stuttering).

About 5% of all children have disfluencies, but only 1% develop persistent developmental stuttering (PDS). I am interessed in how fast the 5% go to the 1% baseline of adulthood. Is it within 1-2 years of stuttering? So after the age of 5 or 7, 80% have recovered.

I am especially interested in the age group 9-13. Can one study therapy effect like in adults, or is there still a natural recovery rate to consider.

If you know of any literature, please let me know.

Yaruss - Onslow (Part II)

the second part of their debate...


Mark,
Regarding future application of theory, you imply that history must repeat itself, whereas I only say that it might. To prevent this, we both highlighted safe-guards, such as that the theory must generate testable hypotheses. Meanwhile, it is true that the data for other treatments are presently lacking–much work remains to be done. To accomplish this, I would like to have, as a starting point, a framework to support that therapy and the necessarily data collection.

Uni-dimensional explanations do not provide an appropriate starting point, for stuttering encompasses more than just speech disruptions, and the factors involved in the onset and development of stuttering involve more than just speech disruptions. Thus, I would challenge your claim that “multifactorial theories of stuttering are completely and irretrievably wrong.” It might help if we were to differentiate between multifactorial theories and resultant (or non-resultant) treatments. Obviously, theories cannot be used to treat stuttering, but they can provide the basis for a testable treatment.

As we move toward collecting the necessary data, we might benefit from starting with a well-constructed theory that provides an explanation of why we might manipulate certain variables. That would then lead to studies, ultimately including clinical trials, that demonstrate the validity and efficacy of a treatment program. Lidcombe has accomplished this goal from an atheoretical perspective, if I read you correctly. I believe the same goal could be accomplished (though this has not yet been the case) from a theory-driven perspective.

Scott,
Yes, a new theory can lead to a new treatment checked by clinical trials. But not through a multifactorial theory.

There is nothing wrong with multifactoriality. Life is multifactorial, so is love, a toothbrush, and so is stuttering. However, arguing that because stuttering is multifactorial, therefore the cause of stuttering must also be multifactorial is an error of logic. This logical fallacy is called the representativeness reasoning: to believe that the nature of effects reflect the nature of causes (see Onslow, Attanasio, & Packman, 1998).


Additionally, multifactorial theories do not do what a theory should do: explain things (Packman & Attanasio, 2004). Why do word and syllable repetitions predominate at the onset of stuttering? Why can stuttering be intractable for a lifetime? Why do those who stutter have problems with tapping finger sequences? And why do those who stutter have the problem while playing wind instruments?


Mark,
I found the list of factors you find relevant to the explanation of stuttering to be enlightening. In developing a theory to explain the phenomena of stuttering, it is appropriate to begin by listing those phenomena. Here are some questions that strike me: Why does stuttering start at a time of rapid expansion in linguistic, motoric, and temperamental aspects of children’s development? Why do people who stutter react to their stuttering in the way they do? Why does the occurrence of stuttering seem to be so closely linked with aspects of language planning in both children and adults? Specifically, why is stuttering not distributed randomly with respect to linguistic, situational, and experiential variables? Why do people who stutter show differences in motoric stability and linguistic processing, even when they are not engaged in speaking tasks? What about differences in neural function and possibly even structure? And temperamental differences? Finally, why do multiple loci seem to be implicated in genetic modeling?

This is not an exhaustive list...just a start of the questions that would need to be answered by any comprehensive theory. Posing a single factor to explain all of this would seem unlikely. Posing multiple, interacting factors gives the opportunity to save more of the phenomena.

Moving back to treatment, I would like to see further discussion of what might be going on for children who do not recover through Lidcombe, and what might be changing in children who do recover through other therapies. This would enhance our understanding of the disorder from both a theoretical and clinical perspective, and it would provide better justification for why we do what we do in therapy. Until we understand the reason for the change in fluency to supplement the basic fact of the change itself, I will remain dissatisfied with the knowledge base and will seek to identify some means of explaining the many and varied phenomena of this disorder.


Scott,
Clinical trials and cohort studies give me no reason to think that there is a group of children who do not respond to the Lidcombe Program. Jones et al. (2000) reported 261 treated children of which 250 completed Stage 1. Thus, 250 children attained zero or near-zero stuttering. The remaining 11 did not complete for reasons common in speech pathology treatments, such as moving away, illness, severe family problems. These findings were replicated by Kingston et al. (2003). A similar picture has emerged with the Phase I, II, and III clinical trials that have been published.

Mark,
Still, questions remain about its real-world effectiveness, for not everyone may administer the program as efficiently or as effectively as you and your colleagues appear to. We have discussed non-responders more than once before. You may not see them in your studies, but I know of other clinicians who see them in their daily practice. Clinicians have consulted with your team and other Lidcombe practitioners, and your team is quite responsive in trying to help clinicians in such cases. So such cases seem to exist.

As for other treatments, in a preliminary study of the approach used at our Stuttering Center (Yaruss et al., in press), we found that 17 out of 17 children enrolled in the program (not just those treated to completion), achieved improved fluency and maintained it over a follow-up period of at least 2 to 3 years. Most required only the 6 sessions that the program is designed around, but a few children required more treatment. Why did the 4 children require more than 10 sessions? Ultimately, these children also recovered, but the lack of immediate success might teach us about the disorder. So, we look at factors like language skills, motor skills, temperament, family history, and life experiences to help us better understand the treatment and the disorder itself. Have you conducted similar inquiries with Lidcombe? What theoretical framework did you use?

Scott,
Again, there is no scientific evidence for the existence of a substantial cohort of non-responders. Also, my position is that the population effectiveness of the Lidcombe Program is currently unknown to science, because no effectiveness research has been conducted. But we have evidence for its efficacy. Epidemiological studies would be needed to address the capacity of the Lidcombe Program to impact at the clinical population coalface. We have put in place various ways to facilitate that effectiveness. For example, a Lidcombe Program Trainers Consortium has been established in seven countries ("Lidcombe Program Trainers Consortium Grows in Europe," 2005). Each year, hundreds of clinicians around the world receive training from Consortium clinicians who meet published scientific benchmarks for the treatment.

If you know of someone who consistently does not get children to stop stuttering with the Lidcombe Program, there are at least two possible reasons. First, they may have not done the treatment according to the manual that can be downloaded from our website. Second, they may benefit from Consortium training in the treatment.

You accept that the LP has the best clinical trials efficacy research. So, what treatment do you select for a four-year-old stuttering child in need of treatment?

Mark,
I treat as described in Yaruss et al. (in press), but I also work to validate that treatment and collect data to refine and improve the treatment. Though I do not use Lidcombe, my staff has received training and we have discussed the principles of the treatment in detail. Furthermore, I always encourage clinicians to participate in the consortium training directly if they are considering using the Lidcombe program. I fear that many might not be using the treatment correctly, and without an understanding of why the treatment should work, it is impossible to know what the results from various modifications might be. This is yet another reason I keep returning to the value of theory, and why I asked the question that started this dialogue.

For my part, before I accept a treatment such as Lidcombe, I want to have a better idea about the nature of the changes that are taking place. Thus, in my clinic, we are actively engaged in examining not only the efficacy of the treatment we use, but also the mechanisms behind the observed changes. Much more work remains to be done, but our work, and that of others, is progressing.

Yaruss vs Onslow (Part I)

Here is the discussion I have been edited for the BSA between Mark Onslow and Scott Yaruss: see here.


Mark,
The diagnosogenic theory stated that stuttering was caused, in part, by parents inappropriately drawing attention to a child’s otherwise normal disfluencies. In recent years, many have commented on the numerous shortcomings of this theory as an explanation for early stuttering, and, in particular, on the negative effects it has had on treatment planning and clinical decision making.

Given your recent research on stuttering treatment, combined with research on early recovery, with what theoretical framework would you replace the diagnosogenic theory, and how would such a theory help to explain basic phenomena associated with childhood stuttering?


Scott,
There should currently be no replacement for the diagnosogenic theory as a driver of treatment for early stuttering. Many theories are available (for an overview, see Packman & Attanasio, 2004), but none of them has proven to be correct, and only one of them—or perhaps none of them—is correct. Hence for the time being, it is a dubious practice to base treatment on any theory of what causes or perpetuates stuttering.

We are all desperate to find out what causes stuttering. But intervention of early stuttering can occur independent of efforts to uncover its cause. For example, the Lidcombe Program is not driven by a theory of the cause of stuttering, and is nonetheless efficacious according to a recently published randomised controlled trial (Jones et al., 2005).


Mark,

Few would doubt the efficacy of the Lidcombe program, as described in numerous publications and the recent clinical trials. Still, some may question its effectiveness in daily clinical settings. Further, is Lidcombe the only way to accomplish our common goal of eliminating stuttering in young children?

Of course, it is true that theory has not always served our field well. Many clinicians still cling to ineffective treatments derived from the long-disproved diagnosogenic theory, but would this necessarily have to be the case with other theories?

Improvements in treatment might still be achieved through the rigorous application of theory-driven clinical research aimed at uncovering factors involved in the onset, development, and maintenance of the disorder. Uni-dimensional theories have proven unsatisfactory throughout the history of our field, so I would start with a theory that incorporates more than one factor as a potential cause for stuttering.

Scott,
I hope that no clinician is still using the diagnosogenic theory to treat stuttering. For example, Bloodstein tried for years to implement the treatment suggested by the theory, but failed completely (see Bloodstein, 1986). I do not think my concerns are an overstatement. A theory of the cause and development of stuttering would certainly be fine as a basis for treatment as you say, but with two provisos. First, the theory is verified with the scientific method. Second, the treatment based on the theory is evaluated with clinical trials of an acceptable standard. Surely it is unethical to provide health care with unproven treatments? The local doctor would not do it for asthma, and neither should the local speech pathologist do it for early stuttering.

Yes, the effectiveness of the Lidcombe program at the population level is not yet well researched. Also, it may not be the only way to treat early stuttering. There might well be other treatments, and I look forward to the publication of clinical trials of other treatments. If clinical trials show that there is a better and quicker treatment, I will be the first to use and endorse it.

However, I would not endorse multifactorial theory of stuttering as a source of treatment development. First, multifactorial theories of stuttering are completely and irretrievably wrong from empirical and logical perspectives. Second, no clinical trial shows the capacity of multifactorial treatments to control stuttering. There is a real risk that the errors of the diagnosogenic era will be repeated if we use multifactorial theories to treat children: that we will think that we know the cause of stuttering when we do not, and that we know what is an efficacious treatment for early stuttering when we do not.

I also do not agree with your claim that one type of theory, such as multifactorial theory, has been more successful than another such as single factor theory. In fact, no theory has been successful in explaining the cause of stuttering (see Packman & Attanasio, 2004).

Nijmengen conference 2006

Three weeks ago, there was a conference in Nijmengen. I will put up the summary of the event, thanks to Oren. More soon...

Neurological stuttering

I just read that 50% of people who have neurological stuttering (after a neurological incident) stuttered as kids. Did the incident destroy or weakened a compensatory mechanism?

Note: Neurological stuttering differs from PDS (persistent developmental stuttering), because it typically occurs in (late) adulthood due to a stroke or accident.

Tell this to a 3-year old

At conferences, I sometimes hear people proclaiming that stuttering has been a gift and inspiration to them. The process of overcoming stuttering has made them stronger and wiser human beings. Indirectly they thereby question my "obsession" with understanding stuttering. Yet others tell me that they are not the least interested why they stutter. Their rationale is: "I stutter. I have no idea why. Why waste time thinking about the why. I will concentrate on what I do now and try to reduce my stuttering." Again, they are no interested in research.

I never quite knew how to reply, as they are not completely wrong, though I felt they were somewhat on the wrong track. Now I have a clear reply: "Yes, overcoming or reducing stuttering makes you a stronger and wiser person. Attending self-help groups, self-reflecting, and doing a therapy makes you grow as a person. And there is no need to understand stuttering and its causes or mechanism. Following an established therapy is sufficient to become more fluent. But, let's go to a 4-year old child. Are you going to tell that child: Dont worry if you stutter, once you have overcome stuttering (after 20 years of pain, despair, and embarrassment), you are a stronger person? Or are you telling him/her that we dont have more effective way to reduce his/her stuttering because you are not interested in understanding stuttering better as it was not important for you personally?"

That is why I want to understand stuttering better!

Stuttering and addiction

Tammy said:

I hate the analogy of comparing stuttering to an addiction. I know various people use it, but if stuttering is caused by a difficulty, say in the basal ganglia, that is to some degree out of the control of the person who stutters, it seems wrong and unfair to encourage punishment for something. I think the comparison of stuttering to something so negative causes so many difficulties, and exacerbates the potential for people to become anxious about their speech as a result of fearing negative evaluation. I prefer analogies where there isn't an implication of fault- for example poor vision- then treatments and strategies are about optimising your abilities (e.g. wearing glassess, doing eye exercises) raher than punishment!

1) I consider most stuttering therapies a behavioural therapy. You need to change your behaviour (the way you speak or stutter). In the short term, behavioural therapies are extremely successful, be it loosing weight, getting off hard drugs like heroin or crack cocaine, stopping smoking, stopping to drink, stay out off crime, and so on. Unfortunately, all these therapies have lousy success rate in the long-term. People in general fall back to their old behaviour, EVEN THOUGH THEY DO NOT WANT TO. We all know that old habits creep in very slowly: "Just a little piece of chocolate", "I am stressed. Oh there is chocolate lying around.", "I am fed up. I on purpose eat chocolate now. I want to punish myself.", or "Great. I have succeeded easting no chocolate anymore. So now, a bit of chocolate is OK." We readily succumb to short-term urges that win out against our long-term goals.

2)I consider that stuttering is based to varying degree on faulty/weak hardware in the brain which kick-starts and feeds the development of secondary symptoms that re-enforce and increase stuttering severity like fear, lack of eye contact, avoidance, tension, and so on. So, we need to undertake a superhuman effort to control our speaking and reduce the secondary symptoms. I also think that a case can be made that all other disorders that are treated with behavioural therapies are also not just bad habits. Being overweight, addicted to drugs, and being criminal are to some degree in our brain in that these people are pre-disposed to such behaviour under the right circumstances. Especially once you are addicted, your brain changes and you absolutely crave for drugs.

3) Bad vision is not a good example, as you do not need to change your behaviour to see better. You should get glasses.

3) I only compare one aspect stuttering to one aspect of addiction, I do not say that we just become to stuttering and that you crave for it as some would like us to to fit their theories. I am talking about the process of getting off stuttering or drugs.

4) When I think about an issue scientifically / intellectually, I do not care what the political implications are or the impact on other people. My mind is not restricted to "political correctness" (what seems wrong to say), so I do wonder why the fastest runners are black, why black kids underperform whereas the Indian minority outperform, why there are so few women in math / science, and why do less women stutter.

5) I am contemplating what is most effective. If it is punishment, so be it. If it is encouragement, so be it.

6) Punishment is not necessarily bad, especially if the person to be punished agrees with it. In a sense, his long-term thinking agrees that his short-term-urges should be punished.

Stuttering makes you sick?

I have been reading about an therapy against alcohol addiction with an unusually high success rate of 50% after five years. The secret is that the recovering alcoholics take a substance that makes them feel physically sick when drinking alcohol. The substance reacts with alcohol and creates a toxic substance.

Maybe that is what is needed, we need punishment when people start stuttering again, but then again staying fluent after a fluency shaping therapy is about keeping up practise rather than about not stuttering (drinking alcohol) again. But in a sense, relapse happens when someone is not using the new speech technique anymore and using the old one (starts the old habit like drinking again).

But here is another twist. They gave one group of alcoholics a placebo (i.e. a pill containing nothing), and they still showed the high success rate!!!! So in a sense you dont need the drug at all but you need a drug that is able to punish for new stuttering!

Pagoclone safe?

A reader to this blog sent me an interesting article on the potential for abuse of Pagoclone. The authors are Harriet de Wit, Lisa Vicini, George M. Haig, Thomas Hunt, and Douglas Feltner (Note that some are associated to Pfizer, which is a rival company of Indevus, the producer of Pagoclone, as far as I am aware of). Briefly, they compare Pagoclone to Diazepam (also an anti-anxiety drug). They suggest that Pagoclone is relatively safe to use with some effect on mood, subjective and objective sedation, similar to Diazepam. And a similar (relatively low) potential of abuse. Though the picture may change a bit as the effect is dependent on the actual dosis.

Judge for yourself...

Evaluation of the Abuse Potential of Pagoclone, a Partial GABAA Agonist

This study assessed the abuse potential of pagoclone, a partial agonist at the g-aminobutyric acid type A (GABAA) benzodiazepine receptor site, in healthy recreational drug users. Twenty-three young adults, who reported past recreational use of sedative drugs or alcohol, participated in 4 sessions during which capsules containing pagoclone (doses: 1.2 mg, the higher end of the proposed therapeutic dose range, and 4.8 mg, a 4-fold higher dose), diazepam (dose, 30 mg), or placebo were randomly administered under double-blind conditions. Subjective ratings of mood, drug effects, and psychomotor tests were completed at regular intervals after ingesting the capsules. On most of the standardized measures of abuse potential, pagoclone (dose, 4.8 mg) was rated as being similar to diazepam. Both drugs increased the ratings of good effects and drug liking. However, pagoclone also produced some adverse mood effects that might limit its potential to be used recreationally, and it produced fewer sedativelike effects on some measures. In general, the results with these doses indicate that the abuse potential of pagoclone is similar to that of diazepam, although its profile as a partial agonist suggests that differences between the drugs may emerge at higher doses.

( from Journal of Clinical Psychopharmacology Volume 26, Number 3, June 2006)

Will power vs pill power

I met up with Carl and Lloyd on Wednesday afternoon at the Metropolitan in New York, and we went to a near-by cafe. It was good to hear that they both enjoy reading my blog.

The discussion was also an interesting one. I was sitting opposite the two, and both are currently in treatment for their stuttering. Carl has done the McGuire course, which is a behavioural theory with coastal breathing being a core technique, and Lloyd took part in the Pagoclone study and is now in an one year open-label extension. Carl, a tidier and more intellectual version of Frank Zappa :-), spoke about how the course has changed his outlook, and about the intense experience that he felt when realising that he could control his stuttering more and the importance of will power. He got a bit over excited about the paradox of completely believing that this is the right way to become more fluent and not being dogmatic that this should help everyone else. I think it is fair to say than neither myself, Lloyd, nor himself did fully understand what he meant! I am sure he will give us a more collected summary of his thoughts here. Carl said that he was a mild to medium severe stutterer, but that he is pretty fluent at the moment. And I have to agree with him. Apart from some coastal breathing, he spoke completely naturally.

Lloyd spoke about his experiences on Pagoclone, and one thing is clear: Pagoclone is no wonder drug. He still has clear blocks and prolongations. On the other hand, I did feel that his stuttering symptoms were clearly visible but of low intensity, a bit like people doing van Ripper. He did not seem to struggle a lot and seemed patiently going through the blocks and prolongations. Now I dont know how he spoke before the trials. Lloyd said that he felt in greater control of his speech, but only after taking the high dose. He also said that family members thought he spoke better on the phone. So his stuttering seemed to have gotten easier, but no cure. I forgot to ask him whether he wants to write a post about his experience, but will do so. He also mentioned that his recordings were probably more positive due to them being taken in a calm room with a nice female speech therapist!

We also discussed whether a combination of a behavioural therapy and medication would be useful. And whether medication can improve to such a degree that it makes stutterers fluent. Intuitively, meeting the two has made me think that medication is probably most suited for more severe stutterer to give them break and allow for more behavioural work. Finally, we talked about relapse, which is the real test for any behavioural therapy.

P.S. Just want to say that these are individual cases not necessary a reflection of a wider population.

Missed meeting and eye contact

I am in NY, but missed my meeting with Carl and Lloyd (readers of my blog and fellow stutterers). I was on time, but couldnt find the piece of paper where I wrote down the bar we were supposed to meet. But there are so many bars and so on at Central Station... :-(

But was excellent training for maintaining eye contact. I was running for half an hour making eye contact with everyone I possibly could in the hope it would be Carl or Lloyd recognising me from the picture on my blog...

Oh well... maybe we can still meet up.

Talking about eye contact... I have a theory that girls think male stutterers are obsessed by breasts. Why? I am often avoiding eye contact by looking a bit down... of course when I talk to a girl, I happen to look at precisely the place I shouldnt be looking at even though I dont want to look there... what a perfect excuse... oh well... :-)

The Stuttering Brain Roadshow

This blog is going on a roadshow. Here are the different cities:

June 1st to June 3th: Pisa (Italy)
June 4th: Frankfurt (Germany)
June 5th to June 7th: New York (USA)
June 8th to June 11th: Boston (USA)

If you wanne meet up, let me know!!! :-)

P.S. I am going to a wedding in Italy, and fly to NY for a consultancy job, and Boston to meet several people.

Were you a stuttering guinea pig?

If you have participated in the Pagoclone trials, I (and I am sure the other readers) would like to hear from you. Either leave a comment or send me an email. I can make the report anonymous on request.

Ideally the report should tell us about:
1. yourself and your stuttering before the trials,
2. about the procedures and your contacts with the trial managers,
3. about your experiences during the trial and comments by others on your speech.
4. whether you would continue on Pagoclone.

It is important that you only report what you have experienced and comments by others. If you also want to share your interpretation of your experiences, it is crucial that you clearly separate them from your experiences. For example: Instead of "I was more fluent while on Pagoclone", "I took the pills and soon after I felt that I spoke more fluent, but did not ask my wife or others for independent feedback. I am fairly confident that I took Pagoclone and not a placebo, because I felt differently and was less anxious. I also think that I truely became more fluent. So I associate my experience of greater fluency to Pagoclone."

Probing Pagoclone EXPRESS

I was told that a manuscript of the Pagoclone study will soon be published with more details, which will also allow a discussion on effect sizes. So we need to wait a bit. In the mean time...

I looked at the press release a bit more, here are my thoughts:

“Indevus has completed what we believe is the largest pharmaceutical trial ever conducted for stuttering and the results are very exciting,” stated Glenn L. Cooper, M.D., chairman, president and chief executive officer of Indevus. “Our results today show that stuttering, a condition with no approved pharmacological treatment, is potentially treatable with Pagoclone. This study was designed as an exploratory trial to follow up on a limited number of observations of the effect of Pagoclone on stuttering during previous anxiety trials. The design of the EXPRESS trial enabled us to evaluate the condition from several clinical perspectives and we believe this provides us with a strong foundation to develop a clinical plan for further development.”

He says a lot without saying anything... He could be French or a politician... :-)

Gerald A. Maguire, M.D., associate professor, department of psychiatry, University of California, Irvine School of Medicine, stated, “Being a person who stutters and a physician who researches and treats stuttering, I am very excited about the results of this trial. As an investigator on this study, I saw first hand the positive impact pagoclone can have on the lives of patients. Consistent with the results of the entire study sample, more than half of my pagoclone treated patients had a clinically meaningful decrease in the severity of their stuttering. Although there is no cure for stuttering, pagoclone holds significant promise as a well-tolerated, effective and viable treatment for the millions of Americans who stutter.”

Jerry Maguire's statement is more revealing. My interpretation of his statement (which MIGHT BE COMPLETELY WRONG!) is the following: He is mostly excited about the trials, because it is the first large scale study that has been done and the drug shows more effects than any other drug but he is not excited because Pagoclone is a cure. And, not all stutterers benefit from Pagoclone, and those who do reduce their stuttering noticeably but do not eliminate it.

8-week, placebo controlled, double-blind, multi-center trial with an open label extension. There were a total of 132 patients randomized in the trial.

They have followed standard procedure.


EXPRESS (the name of the study) used the following measures:

Frequency and Duration Subscale of the Stuttering Severity Instrument Version 3 (SSI-3)
the Stuttering Severity Scale (SEV)
the Subjective Screening of Stuttering (SSS) Severity Subscore
the Clinician Global Impression-Improvement (CGI-I)
the Liebowitz Social Anxiety Scale (LSAS)
the Speech Naturalness Scale (SNS)


They claim that the measures ( SSI-3, SEV, and SSS) are validated stuttering measures.
My question:
What do they mean by "validated"? Have they done a battery of statistical checks to see how consistent the measure is? My experience is that the stuttering measures taken at week 0 are NOT normally distributed, and there are some significant outliers, i.e. some stutterers are extremely disfluent or fluent. A massive improvement of 1-2 extreme stutterers give statistical significant results for the whole group.


For all measures except SEV, the distributions of measured values for the control group and the placebo group were statistically significantly different at p-values ranging from 0.007 to .08; (typically p=0.05 is regarded as "worth noting" as only 1:20 is the result of a statistical fluctuation, and p=0.01 is considered "reliable").
My question:
1) What happens if you give the medication to normal people? I would guess that their CGI-I and LSAS would improve, too?
2) I want to see the effect size, i.e. I want to know how big the effect is.
3) Is the effect only for some people or all people?


The SEV measure is rated by clinicians from "no stuttering" to "extremely severe". They write: "The on-treatment effect of patients receiving pagoclone demonstrated a numerically superior rating versus patients treated with placebo (p=.18)."
My question:
The p-value is quite high, p=.18, which means that there is a 20% probability that the effect does not exist and is due to statistical fluctuation (i.e. chance).


On SSS, they write "The SSS Severity Subscore, measured at week 2, week 4 and week 8, is a validated, patient-rated assessment of stuttering that takes into account specific speaking situations that have taken place over the prior week. Pagoclone produced a statistically significant reduction at week 2 (p=.004) and week 4 (p=.05) and a trend for significant improvement at week 8 (p=.08) as compared to placebo."
My question:
What is interesting is that the p-values go up with time, from p=0.004, to p=0.05 to p=0.08. This makes me a bit suspicious that they experience a high / placebo effect which decreases with time. Listening at the reports from patients, they pretty well all know whether they are on Pagoclone or not, even though it is blind. So they might experience a high in their subjective assessment of fluency. This possibility can be eliminated by 4-months data.

Before I take Pagoclone

... I would set myself 10 criteria that the medication needs to satisfy. Here are they plus my arguments.

1) The drug has been commercially available for 3-5 years without major negative news and gossip. I want to see whether Pagoclone survives the reality test away from random control trials with well-briefed doctors and especially-selected patients. The commercial use must not necessarily be for stuttering.

2) I convinced myself that the effect size is large. Taking any medication is about balancing risks, and I am only willing to take the risks on (known and unknown long-term) side effects if the effect of Pagoclone is significant (not just a bit more fluent) and lasting.

3) I convinced myself that the effect is not just due to what Pagoclone has been designed for anti-anxiety. It is possible that the positive effect claimed is due to the anti-anxiety effect. Effectively, patients know that they are on Pagoclone, because they become more relaxed. And then the placebo effect also sets in, and together greater fluency is achieved. Also, I rarely experience anxiety, and I am wondering what the drug would do to me mentally. Am I going to turn into a wild inhibited animal? :-)

4) I convinced myself that a scientific study of long-term user of Pagoclone has shown minimal and reversible side effects. My stuttering does affect my life and reduces my potential in certain situations, but I do not think I would trade more fluency with weight gain, headaches, or other effect lightly.

5) The FDA has made a positive statement on side effects and for use to treat stammering. But I would still be hesitant. I spent a lot of efforts to understand stuttering, and the issues are damm complex. So I cannot see how the generalist FDA would understand the issue better, on the contrary. So I would not trust them on what they have to say about its use for treating stuttering, but most certainly on their statements regarding side effects.

6) Neurologists or other related experts not linked in any way to Indevus recommend its use. Stuttering is potentially a multi-million market, and a lot of recognition for the involved researchers / doctors. Also, Indevus has spent a lot of money on these trials. This is just a precaution, and a best practise in any risk management. Wishful thinking and money are always a very strong motivator to twist and spin. Always ask outsiders for a second opinion.

7) Neurologists or other related experts who STUTTER themselves use Pagoclone to treat their own stuttering!!!! :-) This would be strong evidence that Pagoclone is effective and safe. They are professionals and know the realities, and are able to make a much better judgement call than myself.

8) The hype and discussions on Pagoclone are over. Currently, we are in a hype period. News came out, and many journalists are picking it up. They are no experts, and need to simplify issues for the reader. So expect white and black comments rather than greyish. Such comments will be taken on, and this will lead to strong clear-cut opinions being formed. So it is always best to wait for things to cool down until everyone is bored about it!!

9) I have personally spoken to 2-3 people who took / are taking Pagoclone. Scientific studies are crucial, but talking to actual people is a very insightful reality check.

10) Pagoclone does not delay or inhibit ejaculation. Indevus wants to sell Pagoclone to treat men with pre-ejaculation. Then the question arise whether normal man are also impacted? If so and in a significant way, I would need to think hard about this one.