Monday, June 18, 2007

Guest-Blogger Willme on why ativan might work for him (II)

Let’s try to understand what’s happening from the research perspective. Given that ativan 2mg has worked so well for me, I am puzzled that no one else among the estimated 3,000,000 stutterers in this country has discovered its efficacy. Am I the only one for whom this drug therapy works? If it works for other stutterers, for what fraction of them is ativan effective? Is what I’m experiencing a placebo effect whereby I go from some level of disfluency to virtually a zero score on the stuttering severity instrument?
Ativan (technically known as lorazepam) is a benzodiazepine (BZ), which binds to the BZ receptors in the brain. BZ receptors seem to be coupled to receptors for the inhibitory neurotransmitter gamma amino butyric acid (GABA), which is the most prevalent neurotransmitter in the brain. BZ and GABA receptors coexist together in an interactive complex known as GABA-BZ (Receptors, Restak, R.M., Bantam Books, 1994, pp 166-167). BZ’s (the most notorious of which is valium), inhibit anxiety just like GABA. So ativan is regarded as a GABA agonist since it binds to GABA-BZ receptors and when it does neurons are less likely to discharge. Correlates of anxiety involve excitation (more rapid firing of neurons) and BZ’s reduce this excitation. By the way, previous studies have shown the ineffectiveness of BZ’s with respect to improving fluency (The pharmacology of stuttering: a critical review, Am Journal Psychiatry. 1991 Oct; 148(10):1309-16.Brady JP). One of the studies cited in this review that I acquired used valium (diazepam) at 5 mg dosages. I don’t know what the conversion over to ativan dosages is.
Now most of you have heard of pagaclone, currently in phase III trials as a palliative for stuttering. Pagaclone is identified as a partial GABA agonist, the “partial” referring to its lack of sedative and withdrawal effects. It too binds to the BZ receptors. The most recent press release of Indevus Pharmaceuticals indicates that phase II trials have been a roaring success in reducing disfluency. The way that pagaclone was identified as a potential palliative for stuttering was that in previous trials testing it as an anti-anxiety agent there happened to be at least one stutterer in the test group and he (she, they) reported a marked improvement in fluency levels. So to answer one of my questions above, there are at least two of us who recognize that GABA agonists/partial agonists may greatly improve fluency. To my knowledge, pagaclone was never released as a prescription drug to treat anxiety (in spite of claimed success in the anti-anxiety trials), so the possibility does not exist for our buying it and using it off label for disfluency.
A second major research direction in the current pharmacological treatment of stuttering. involves basal ganglia/dopamine system (BG/DS) theories. This line of research seems to be mutually exclusive from the GABA/pagaclone efforts or, at least, researchers have not yet found any connection between them. The BG/DS theories revolve around malfunctions in the basal ganglia very deep in the brain and the presumed production of too much dopamine, which is another neurotransmitter. Dopamine is associated with addictive illegal drugs, Parkinson’s disease (a lack of dopamine), and reward systems. Risperidone is a dopamine antagonist and has been claimed to improve stuttering in clinical trials (for a good review,see Stuttering and the Basal Ganglia Circuits: A Critical Review of Possible Relations, Alm, P. in Journal of Communication Disorders 37, 2004, pp 325-369). This review article also cites studies in which stimulants were used to increase dopamine resulting in improved fluency. So the author of this article concludes that there may be two types of stutterers, ones who improve on dopamine antagonists and others who become more fluent on dopamine stimulants.
Incidentally, I’ve tried the antianxiety drug Buspar which binds to dopamine receptors ( a moderate affinity for D2-dopamine receptors) and reduces the influence of dopamine (a dopamine antagonist?). I found it has no effect on either my fluency or my anxiety. Fifteen minutes after ingesting the drug I get a buzz in the brain and feel spacey for about half an hour. And even more incidentally, I’ve tried a variety of antidepressants (serotonin uptake inhibitors only) and these have had no effect on me whatsoever.
So the question is: Are there indeed different subclasses of stutterers who respond to different treatments—those with not enough GABA, those with too much dopamine, those with not enough dopamine, etc. Having trained as a scientist, I would prefer to follow the “law of parsimony,” and try to explain a phenomenon with a single theory rather than a collection of theories. But nature may not be so neat. If the subclasses of stutterers multiply, then it may be very difficult to get positive results from clinical trials. For example, if only some fraction, F, of stutterers respond to pagaclone, and that fraction F is too small (say less than 10%), then the trials may not be able to identify significant differences between the group receiving the drug and the one receiving a placebo. In addition, if the fraction is too small, the drug company may feel it not worthwhile to market the drug.
To answer the question as to whether the fantastic results that I experience with ativan 2mg is a placebo effect, I have some anecdotal evidence to offer. Several times before teaching my 3 hour graduate class I had forgotten to take the ativan and found at the start of class that I was disfluent. After several minutes of this I realized what the problem was. The second bit of evidence occurred at a conference in Texas at which I was giving a presentation. The presentation was scheduled just after lunch and prior to the presentation I had a Tex-Mex meal which impeded the ingestion of the ativan that I did take after the meal but before the presentation. Once again—a lack of fluency. While this evidence isn’t as good as a controlled double blind experiment, at least I’m convinced that we don’t have a placebo effect in play here.
Given my experience, you can understand my enthusiasm for the pagaclone trials. Like most of you I’m impatient to try it, but I think it will be more than a year before it comes on market, if indeed it reaches market. Then we’ll have to worry about price gouging by the pharmaceutical industry.

NOTE: PLEASE CONSULT WITH A DOCTOR BEFORE TAKING ANY MEDICATION TO TREAT STUTTERING!