Would you take a drug to reduce stammering if you could? In June 2006, tests of a new drug showed positive results, but how close is it to being available? Martin Sommer reports on the study led by professor Gerald Maguire (a keynote speaker at the BSA Conference 2006), and on the background to drug research.

Professor Gerald Maguire, who has been leading research on drugs to reduce stammering.

The 1950s not only heard Marilyn Monroe's beautifully whispering voice, but also saw the first wave of drug trials for the treatment of stuttering. Haloperidol, a then rather new drug for psychiatric disorders, was studied in various trials and claimed to be successful (1). However, its side effects and the rise of behavioural rather than biological theories of stuttering were key factors to prevent a widespread application of haloperidol in stuttering people, at least in the western world.

Today, new psychiatric drugs with fewer side effects exist, and modern brain imaging provides new and fascinating insights into the stuttering brain. It is therefore not surprising, that a second wave of drug trials in stuttering has just started and is likely to go on for some time. Fortunately, the quality of clinical pharmaceutical trials is much higher now than it was in the 1950s.

How drugs are tested

A key new element in current tests are placebo (or control) groups: a part of the patients on the trial do not receive the pharmacological compound but a placebo (or the sugar pill). The random control trial studies are double blind (patients and doctors do not know who gets the active compound or the sugar pill) and randomised (the dice decides which patients get the active compound). This set-up serves to rule out unspecific benefits of expectation, which can be surprisingly huge.

In addition, regulatory authorities require a solid, four-step licensing procedure to avoid catastrophic side effects (2). After pre-clinical trials on animals, phase I clinical trials are safety trials on healthy subjects which can go terribly wrong, as recently seen at Northwick Park Hospital in London (3). Phase II trials are the first time when a group of usually less than hundred patients suffering from a particular condition take the drug or the placebo to measure its clinical effect, its side effects and the appropriate dose range. About 80 % of the drug developments fail due to too strong side effects or lack of effectiveness. Phase III trials encompass several hundred patients. If these trials are positive and the compound is accepted for a disease by regulatory authorities such as the European Agency for the Evaluation of Medicinal Products (EMEA) and the Food and Drug Administration (FDA) in the USA, phase IV trials continue during the marketing of the drug to detect rare side effects. Phase IV trials can abruptly terminate a drug's career, as seen for the anti-inflammatory drug rofecoxib (Vioxx®).

Drugs to reduce stammering

Professor Maguire from the University of California at Irvine and his team were the first to undertake double-blind placebo controlled studies for risperidone (4) and olanzapine (5) on small groups of 16 and 22 adults with stuttering, respectively. These investigator-initiated trials are similar to phase II trials. Half of the subjects received placebo, the other half the active compound. They measured the percent of syllables stuttered in either trial, and took additional subjective scores like patient's perception of speech fluency in the olanzapine trial. They found the active drug of either trial to be superior to placebo in reducing the percent of syllables stuttered. Side effects of these drugs included sedation and lack of menstrual periods for risperidone, and sedation and weight gain for olanzapine. Risperidone and olanzapine have been commercially available for several years now and many patients for psychiatric indications take them. Unexpected side effects are therefore less likely.

The latest tests

This June, Indevus Pharmaceuticals, Inc. announced results from a phase II trial of pagoclone in 132 adults with persistent developmental stuttering, with 44 receiving the active compound at low doses, 44 at high doses, and 44 receiving a placebo (6). Objective fluency improved (videotaped and scored by independent raters blinded) and so did subjective assessment scores (made by the participants in the trial). They were measured twice before the start of the trial, after 4 weeks and again after 8 weeks of treatment. 55% of the pagoclone treated patients had improved at week 8 compared to 36% of placebo treated patients.

Further details such as the effective dose are missing in this company statement (6), as is a peer-reviewed article on this report in a scientific journal. Pagoclone is said to have been well-tolerated with headache and fatigue as the most frequent side effects. The eight-week blinded study period has been followed by an ongoing open-label extension study in which most original patients are said to participate (6).

Why pagoclone?

As far as the author is aware, pagoclone was never commercially available, nor has it ever succeeded in a phase III trial, and knowledge about side effects from phase IV trials is non-existent. Though pagoclone was initially studied for anxiety disorders in larger trials by Pfizer, Inc., Pfizer is said to have "discontinued development of the compound in June 2002" (7). The only phase III trial initiated by Pfizer, Inc., in August 2000 for panic disorder (7) was not available on the Medline (8) as of July 16, 2006, which suggests that it has been stopped. However, these larger trials led to two unexpected observations, one of which was reduced stuttering in patients enrolled for their anxiety who happened to stutter. These potentially interesting findings are now being further studied as primary outcome measures in specifically designed clinical trials, this time by Indevus, which seems to have taken over the rights of the compound from Pfizer (9).

The next stage

To establish a clear efficacy in alleviating stuttering and to obtain EMEA and FDA regulatory approval, larger phase III trials are necessary for both compounds, where hundreds of patients would be studied. These are very expensive and less likely to be financed for risperidone or olanzapine than for pagoclone, because the patent protection for the former drugs will cease soon.

Pharmacologically both drugs have very different properties. Risperidone and olanzapine block the receptors of the neurotransmitter dopamine in the brain, thereby modulating the balance of excitation and inhibition, as excellently reviewed by Alm (10). Pagoclone has a completely different target, binds to so-called GABA receptors and enhances inhibition in the brain (11). These very different mechanisms suggest that different subgroups of stuttering patients may profit from different drugs (10), or that the pagoclone effect is a side effect of its anxiousness-reducing properties.

Taken together, there is a new wave of pharmacological trials in stuttering, with three pivotal trials likely to qualify as phase II trials. All claim positive results, the risperidone and the olanzapine trials are published in peer-reviewed journals, for the pagoclone trial we are so far left with company statements (6) and patent applications (12) primarily addressing shareholders rather than the scientific public.

In conclusion, should we take any of these drugs? Marilyn Monroe's life (and that of many other stutterers) tells us of great success even with a prominent stammer, but also that swallowing too many ill-defined pills does not necessarily make you happy. However, stuttering does severely impair social abilities and their pursuit of happiness for some of us. Good drugs may help, and the currently available data on risperidone, olanzapine and pagoclone raises hopes that need to be validated by large phase III studies.

References
1 Brady JP. The pharmacology of stuttering: A critical review. Am J Psychiatry 1991;148:1309-1316.
2 http://en.wikipedia.org/wiki/Clinical_trial; retrieved July 16, 2006
3 http://news.bbc.co.uk/2/hi/uk_news/england/london/4811626.stm;
retrieved July 15, 2006
4 Maguire G.A et al. Risperidone for the treatment of stuttering. J Clin Psychopharmacol 2000;20:479-482.
5 Maguire GA et al. Olanzapine in the treatment of developmental stuttering: A double-blind, placebo-controlled trial. Ann Clin Psychiat 2004;16:63-67
6 http://thestutteringbrain.blogspot.com/2006_05_01_thestutteringbrain_archive.html;
retrieved July 16, 2006
7 Bateson A. Pagoclone Indevus. Curr Opin Investig Drugs 2003;4:91-5.
8 www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed;
9 www.indevus.com/product/pagaclone.asp?page=pagaclone ; retrieved July 16,
2006
10 Alm PA. Stuttering and the basal ganglia circuits: a critical review of possible relations. J Communic Disord 2004;37:325-369
11 Atack JR. The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics. Expert Opin Investig Drugs 2005 May;14:601-18.
12 www.patentstorm.us/patents/6855721.html; retrieved July 17, 2006

About the author: Dr Martin Sommer is based at the department of Clinical Neurophysiology, University of Göttingen, Germany. His research areas cover movement disorders, with a focus on Parkinson's disease and stuttering.

Acknowledgements: Thanks to Tom Weidig for assistance with this article and for providing feedback. www.thestutteringbrain.blogspot.com

From the Autumn 2006 edition of Speaking Out, pages 6-7