Neurology -- Correspondence for Lucetti et al., 60 (12) 1995-1997

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Correspondence published:

Reply to Heckman et al: Ubaldo Bonuccelli (3 February 2004)

IV amantadine improves chorea in Huntington’s disease An acute randomized, controlled study: Jeannine M Heckmann, Patricia Legg, Diane Sklar, Jennifer Fine, Alan Bryer, Bryan Kies (3 February 2004)

Reply to Heckman et al 3 February 2004

Ubaldo Bonuccelli,
Dipartimento di Neuroscienze Universita di Pisa
Via Roma 67, 56126 Pisa, Italy
Send Correspondence to journal:
Re: Reply to Heckman et al

u.bonuccelli{at}neuro.med.unipi.it Ubaldo Bonuccelli

In our study, [1] a reduction of dyskinesia scores in HD patients was reported both during acute double-blind IV amantadine/placebo administration and after oral amantadine open label chronic treatment. No change in cognitive function or behavior were reported in our series after 12-month chronic administration of amantadine.
Similar results on motor and cognitive function in Huntington disease were observed in another 2-week randomized, controlled study with oral amantadine by Verhagen Metman et al. [2] Previous, uncontrolled studies on the use of amantadine in the treatment of choreic hyperkinesias showed contradictory results with positive [4] or negative effect. [5]
A recent report indicates that amantadine treatment has no significant effect on the score for Huntington’s chorea, although most patients felt subjectively better for choreatic movements. [6] The different results observed may be due to: diversities of statistical methods, daily doses of amantadine, and scoring methods. In particular, the assessment of chorea may be problematic despite the use of valid rating scales and a rigid protocol. Variables such as performance anxiety must be considered. For this reason we evaluated the AIMS score of our patients after 10 minutes of sitting quietly in a chair and always as an average of three different postural conditions (sitting, standing and walking) with and without mental activation.
Moreover, pharmacokinetics factors may play a role. Since plasma amantadine concentrations correlate with chorea improvement [2], we hypothesize that in nonresponder patients, plasma amantadine concentrations might be not sufficiently high enough to reach the therapeutic threshold. This suggests that higher amantadine dosage should be tried, especially in short-term, smaller studies.
The improvements in subjective [6] and objective measures [1,2] of chorea, the positive effect on behavioral scores found by Heckmann et al., and the low side-effect profile indicate that amantadine may be useful in the treatment of Huntington disease. Larger, controlled cohort studies might confirm this.
References
1) Lucetti C, Del Dotto P, Gambaccini G, et al. IV amantadine improves chorea in Huntington’s disease. An acute randomized, controlled study. Neurology 2003;60:1995-1997.
2)Verhagen Metman L, Morris MJ, Farmer C, et al. Huntington’s disease: a randomized, controlled trial using the NMDA-antagonist amantadine. Neurology 2002;59(5):694-699.
3)De la Fuente-Fernandez, Ruth TJ, Sossi V, et al. Expectation and dopamine release: mechanism of the placebo effect in Parkinson’s disease. Science 2001;293:1164-1166.
4)Scotti G, Spinnler H. Amantadine and Huntington’s chorea. N Engl J Med 1971;285:1325-1326.
5)Gray MW, Herzberg L, Lenman JAR, Turnbull MJ, Victoratos G. Amantadine in chorea. Lancet 1975;2 (7925):132-133.
6)O’Suilleabhain P, Dewey RB. A randomized trial of amantadine in Huntington disease. Arch Neurol 2003;60:996-998.

IV amantadine improves chorea in Huntington’s disease An acute randomized, controlled study 3 February 2004

Jeannine M Heckmann,
University of Cape Town
Division of Neurology E8-74, Groote Schuur Hospital, Observatory, 7925, South Africa,
Patricia Legg, Diane Sklar, Jennifer Fine, Alan Bryer, Bryan Kies
Send Correspondence to journal:
Re: IV amantadine improves chorea in Huntington’s disease An acute randomized, controlled study

jheckman{at}uctgsh1.uct.ac.za Jeannine M Heckmann, et al.

A recent article reported a reduction in Huntington’s disease (HD) associated dyskinesia with oral amantadine. [1] We performed a similar study, albeit smaller, with different results. In a double- blind, placebo-controlled crossover study approved by the University of Cape Town ethics committee, the efficacy of amantadine as an antidyskinetic agent in patients with HD was assessed. The two 6-week study arms were interspersed with a 2-week washout period. The ceiling dose of amantadine was 300mg reached at week three. Only subjects in good health were enrolled. Those receiving anti- psychotics, anti-depressants or hydrochlorothiazides were excluded. Only eight patients (three women and five men) were enrolled (2001-2003) and randomly assigned to either arm using computer-generated numbering allocation. Medication (identical capsules containing 100 mg amantadine or placebo) was issued by the blinded treating doctor. This physician also questioned patients by phone about adverse events during the study period. The same two independent blinded observers performed the clinical scoring on the first and last day of each block. The subjects’ median age was 49 years (range 30-63), duration of symptoms 6 years (range 1-10) and CAG repeat size 45 (42-54). The median baseline Unified Huntington’s Disease Rating Scale score (motor assessment, items 4 -7, 14 and 15; behavior assessment, items 1-14) was 47 (9-54) and abnormal involuntary movement scale (items 1-10) was 19 (8-37).
Six patients completed both arms; one withdrew after amantadine (lack of response) and another after placebo (increasing depression). The patients correctly predicted whether they were receiving amantadine or placebo after eight of the 14 trials completed. The overall scores showed an 18% median improvement on amantadine compared to 0% by placebo. However, this was due to an improvement in behavior scores (amantadine improvement 21%; placebo deteriorated 7%) rather than motor dyskinesia scores (amantadine deteriorated 9%; placebo improved 8%). Although the results did not reach statistical significance, important difficulties with outcomes assessments are highlighted.
Not unexpectedly, initial performance anxiety appeared to exaggerate dyskinesia; patients completing both arms showed worse motor scores at the start of phase 1 (median motor =54; behavior =31) compared to that of phase 2 (median motor =48; behavior =30). This may further be complicated by the “expectation of a reward” placebo effect observed in diseases affecting dopaminergic systems. [2] Similar to earlier reports [3,4] oral amantadine did not show a consistent anti-dyskinetic effect in HD patients. In those who objectively improved, it was mainly in the behavioral scores. However, the sample size was small. The dose was slightly lower than that given by Verhagen Metman et al. who suggested a dose-dependent effect [5], although our dose was equal to the doses given by Lucetti et al. [1]
References:
1. Lucetti C, Del Dotto P, Gambaccini G, Dell’Agnello G, Bernardini S, et al. IV amantadine improves chorea in Huntington’s disease. An acute randomised, controlled study. Neurology 2003;60:1995-1997.
2. De la Fuente-Fernandez, Ruth TJ, Sossi V, Schulzer M, Calne D, Stoessl AJ. Expectation and Dopamine Release: Mechanism of the Placebo Effect in Parkinson’s disease. Science 2001;293:1164-1166.
3. Scotti G, Spinnler H. Amantadine and Huntington’s chorea. N Engl J Med 1971;285:1325-1326.
4. Gray MW, Herzberg L, Lenman JAR, Turnbull MJ, Victoratos G. Amantadine in chorea. Lancet1975;ii:132-133.
5. Verhagen Metman L, Morris MJ, Farmer C et al. Huntington’s disease: A randomized, controlled trial using the NMDA-antagonist amantadine. Neurology:2002; 59: 694 - 699.