therapeutic interventions for symptomatic treatment in ......doi: 10.1002/14651858.cd006456.pub2...
TRANSCRIPT
Therapeutic interventions for symptomatic treatment in
Huntington’s disease (Review)
Mestre T, Ferreira J, Coelho MM, Rosa M, Sampaio C
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2009, Issue 3
http://www.thecochranelibrary.com
Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
10DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Amantadine, Outcome 1 Change in maximal chorea (%). . . . . . . . . . . . 41
41WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iTherapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]
Therapeutic interventions for symptomatic treatment inHuntington’s disease
Tiago Mestre1, Joaquim Ferreira2, Miguel M Coelho2, Mário Rosa1, Cristina Sampaio2
1Neurological Clinical Research Unit, Institute of Molecular Medicine, Lisboa, Portugal. 2Laboratório de Farmacologia Clínica e
Terapêutica, Faculdade de Medicina de Lisboa, Lisboa, Portugal
Contact address: Tiago Mestre, Neurological Clinical Research Unit, Institute of Molecular Medicine, Hospital de Santa Maria, Av.
Prof. Egas Moniz, Lisboa, 1649-028, Portugal. [email protected]. (Editorial group: Cochrane Movement Disorders Group.)
Cochrane Database of Systematic Reviews, Issue 3, 2009 (Status in this issue: New)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DOI: 10.1002/14651858.CD006456.pub2
This version first published online: 8 July 2009 in Issue 3, 2009.
Last assessed as up-to-date: 22 December 2007. (Help document - Dates and Statuses explained)
This record should be cited as: Mestre T, Ferreira J, Coelho MM, Rosa M, Sampaio C. Therapeutic interventions for symp-
tomatic treatment in Huntington’s disease. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD006456. DOI:
10.1002/14651858.CD006456.pub2.
A B S T R A C T
Background
Huntington’s disease (HD) is an orphan autosomal dominant neurodegenerative disorder caused by the amplification of a nucleic acids
triplet repeat. It is characterised by core symptoms of chorea, progressive dementia and psychiatric manifestations such as depression,
irritability, apathy and psychosis. In current clinical practice, drugs exist that seem to improve symptoms for HD patients. However,
their effectiveness has not been fully measured.
Objectives
To evaluate the effectiveness of the available interventions for the symptomatic treatment of HD.
Search strategy
The search strategy developed for the Movement Disorders Group was undertaken. Cochrane Controlled Trials Register, Medline,
EMBASE and Clinical Trials Database of the United States National Institute of Health were thoroughly searched up until December
2007.
Selection criteria
All randomised, double-blinded, placebo-controlled clinical trials conducted on any symptomatic therapy used for HD with at least
ten participants were included. Participants should have HD clinical features and a confirmatory genetic diagnosis or a compatible
family history. All disease variants and ages of disease onset were included. Cross-over studies were included. All pharmacological and
non-pharmacological interventions aimed at the control of signs and symptoms associated with HD were to be selected.
Data collection and analysis
Two reviewers independently assessed the identified trials for eligibility. In the selected trials, the assessment of their methodological
quality was done according to the Cochrane Collaboration handbook, and eligible data were registered onto standardised forms. If
possible, an intention-to-treat analysis was conducted. When data were not available in the original publication, the principal investigator
of the trial was contacted. A meta-analysis was conducted when possible and otherwise the descriptive summary of the results was
provided. The software Revman 5.0.15 was used for statistical analysis.
1Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results
22 trials (1254 participants) were included. Nine trials had a cross-over design and 13 were conducted in parallel. Study duration
ranged from 2 to 80 weeks. Various pharmacological interventions were studied, mostly, they were anti-dopaminergic drugs (n = 5),
glutamate receptor antagonists (n = 5) and energy metabolites (n = 5). Only tetrabenazine showed a clear efficacy for the control of
chorea. The remaining pharmacological interventions revealed no clear effectiveness.
Authors’ conclusions
No intervention proved to have a consistent symptomatic control in HD. Tetrabenazine is the anti-choreic drug with the best quality
data available. Other symptomatic areas should be explored by well-designed randomised placebo-controlled studies.
P L A I N L A N G U A G E S U M M A R Y
Interventions to control symptoms in Huntington’s disease
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease. No curative therapy is currently available. We proposed
to assess the effectiveness of interventions aimed at controlling the symptoms of HD and to analyse the methodological quality of
the corresponding clinical trials. 22 trials were identified. The review of these trials comprising 1254 HD patients revealed that no
intervention produced a robust conclusive symptomatic effect. Nevertheless, tetrabenazine was the drug for which better data exists
supporting a beneficial effect in the treatment of chorea. There were no available data for the specific treatment of other clinical relevant
problems associated with HD such as depression, irritability, apathy, cognitive impairment or psychosis.
B A C K G R O U N D
HD, also known as Huntington’s chorea, was first described by
the eponymous North American physician George Huntington in
1872 (Lanska 1995). It is characterised by choreiform movements,
progressive dementia and psychiatric manifestations (depression,
psychosis, apathy, irritability). Choreiform movements consist of
involuntary, rapid, irregular, jerky motor actions, including facial
twitching or writhing, and twitching of distal extremities, but also
may manifest itself in more generalised forms that can impair gait
(Ropper 2005). HD is an autosomal dominant inherited disease,
meaning that the child of an affected patient has a 50 % chance to
develop the disease. The causative gene is located in chromosome
4 and encodes a protein known as huntingtin (TH s DCR Group
1993). Huntingtin gradually accumulates within brain cells, caus-
ing damage and cell death in certain brain areas, namely the basal
ganglia and neocortex. The rate of accumulation of huntingtin
is associated with the number of repeats of a specific sequence of
three nucleic acids (CAG). A greater number of repeats is associ-
ated with an earlier disease onset (Kieburtz 1994). HD is encoun-
tered throughout the world and in all ethnic groups. The global
prevalence of HD is estimated to be 4-5 per one million people. In
western countries it is estimated to be 8-10 per 100.000 people.
There is no gender predominance. HD usually begins between
the ages of 30 to 50 and determines death 15 to 20 years after the
onset of neurological manifestations (Ropper 2005). An early on-
set variant exists (Juvenile HD or Westphal variant) and typically
begins in adolescence. In contrast with the adult form, it manifests
with slowness of movement (bradykinesia) and increased muscu-
lar tone (rigidity type). It presents a more severe course with an
average survival of 5 to 10 years (Ropper 2005) after the onset of
disease.
In current clinical practice, there is a broad spectrum of therapeu-
tic interventions proposed for the symptomatic treatment of HD
(Bonneli RM 2005). However, the rational for its use comes es-
sentially from clinical practice and by the extrapolation of results
obtained in interventional studies performed in other neurological
diseases. This scenario calls for a critical appraisal of the efficacy
and safety of all proposed symptomatic therapeutic interventions
conducted specifically for the treatment of HD.
Preliminary examination of the literature also suggests a wide vari-
ation in the design, outcomes and quality of studies evaluating
therapeutic interventions, which further underlines the need for a
systematic review of the most reliable evidence. The present review
critically analyses the best available clinical data about therapeutic
interventions applied to the control the symptoms of HD.
O B J E C T I V E S
Evaluate the effectiveness of therapeutic interventions aimed at
controlling the symptoms of HD.
2Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
M E T H O D S
Criteria for considering studies for this review
Types of studies
All randomised, controlled, clinical trials of therapeutics investi-
gated for the symptomatic control in HD. Trials with less than
ten patients were excluded as well as those in which allocation was
not adequately concealed.
Types of participants
Participants with HD clinical features and a confirmatory genetic
diagnosis or a compatible family history. All disease variants and
all ages of disease onset were included. All possible concomitant
therapies were accepted.
Types of interventions
All pharmacological and non-pharmacological interventions
aimed at controlling signs and symptoms associated with HD were
selected. For clinical problems in which no placebo-controlled tri-
als could be found, we allowed the inclusion of randomised com-
parisons of pharmacological interventions for which a ’standard’
treatment is consensually accepted by the medical community to
have a degree of efficacy for the treatment of a specific problem
(for example, classical neuroleptics for the control of chorea).
Types of outcome measures
Primary outcomes
1. Effect on depression (measured by patient-rated scales
such as the Beck Depression Inventory or by clinician-
rated scales, such as the Hamilton Rating Scale for De-
pression).
2. Effect on cognition measured by performance on ob-
jective tests of cognitive function [for example, mem-
ory, attention, name-finding, speed of processing or
global measures such as Mini Mental State Examina-
tion (MMSE) or Alzheimer´ s Disease Assessment Scale
- cognitive subscale(ADAS-cog)].
3. Effect on chorea/dyskinesias measured by quantita-
tive scales like Abnormal Involuntary Movement Scale
(AIMS) or Unified Huntington’s Disease Rating Scale
(UHDRS) (Table 1).
Table 1. Unified Huntington’s Disease Rating Scale (UHDRS)
COMPONENTS items evaluated
Motor Assessment oculomotor function, dysarthria, chorea, dystonia, gait, postural stability.
Cognitive Assessment phonetic verbal fluency test, Symbol Digit Modalities Test, the Stroop Test.
Behavioral Assessment affect, thought content, coping styles.
Functional Assessment Independence Scale, (checklist of common daily tasks) Total Functional Capacity (TFC).
HSG 1996
1. Effect on behavioural disturbance and psychosis.
2. Effect on functional performance measured by func-
tional scales like the Total Functional Capacity (TFC)
subscale of the UHDRS( Table 1).
Secondary outcomes
1. Physician and/or patients´ global clinical impression.
2. Quality of life measured by generally accepted scales
(e.g. SF-36).
3. Change in burden for patient caregiver (e.g. caregiver
questionnaires).
4. Death.
5. Tolerability of treatment measured by withdrawal from
trials.
6. Safety measured by the incidence and nature of adverse
effects, the occurrence of adverse effects leading to with-
drawal and serious adverse effects defined as any adverse
event that is life-threatening or results in death, hospi-
talisation or prolonged incapacity/disability.
Search methods for identification of studies
Electronic searches
We identified trials from the following databases:
3Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1. Cochrane Controlled Trials Register (Central/CCTR in
The Cochrane Library, Issue 4, 2007);
2. MEDLINE (1966 to December 2007);
3. EMBASE (1974 to December 2007);
4. Clinical Trials Database of the United States National
Institute of Health (December 2007)
For MEDLINE and Cochrane Controlled Trials Register, we used
the following MeSH search strategy:
1. huntington/all subheadings
2. chorea/all subheadings
3. drug therapy
4. prevention and control
5. rehabilitation
6. surgery
7. therapy
8. psychology
9. mortality
10. #1,2 AND #3
11. #1,2 AND #4
12. #1,2 AND #5
13. #1,2 AND #6
14. #1,2 AND #7
15. #1,2 AND #8
16. #1,2 AND #9
17. 10-16
18. #17 AND limit: clinical trial
19. in humans
No language restriction was applied. If necessary, the translation
of the original article to Portuguese was done.
Searching other resources
We also:
1. Searched referenced lists of identified trials and HD
review articles;
2. Hand searched the Movement Disorders Journal and
abstract books of international congresses of movement
disorders and dementia;
3. Personally contacted other researchers in the field;
4. Contacted drug manufacturers in order to obtain addi-
tional information on trials identified in other sources
or unpublished trials.
Data collection and analysis
The studies identified by the search strategy were independently
assessed by two of the authors (Mestre T, Ferreira J) in terms of
eligibility. Disagreements about study inclusion were resolved by
consensus between Mestre T, Ferreira J and a third party (Coelho
M).
The selected studies were independently assessed for methodolog-
ical quality by two of the authors (Mestre T, Ferreira J) accord-
ing to the Cochrane Handbook for Systematic Reviews of Inter-
ventions (Cochrane 2008). Data analyses were recorded regard-
ing randomisation methods, treatment and assessment blinding,
comparability of treatment groups in terms of demographic and
clinical characteristics (age of onset, disease duration and severity,
CAG repeat expansion, co-morbidity, concomitant medication),
inclusion and exclusion criteria, number of drop-outs or losses to
follow-up and corresponding causes, duration of follow-up, defi-
nition of outcomes, use of validated scales and description of ad-
verse events. The Jadad score was used as a global measure for
methodological quality (Jadad 1996). We decided to exclude trials
with a Jadad score <3.
Possible sources of bias were considered, namely: 1) selection bias,
including randomisation and random difference between groups
due to small sample size; 2) performance bias; 3) attrition bias; 4)
detection bias, including modification of validated rating scales;
5) selective report of results.
Two of the authors (Mestre T, Ferreira J) independently registered
eligible data onto standardised forms and cross checked them for
accuracy. Disagreements between authors were resolved by con-
sensus between Mestre T, Ferreira J and a third party (Coelho M).
When appropriate, data from within and between studies were
pooled. Accordingly, we calculated the mean difference for contin-
uous outcomes measured with the same scale and the standardised
mean difference for continuous outcomes measured on different
scales. A random-effects model was used. Clinical and statistical
heterogeneity was explored considering the methodological qual-
ity of the trials, treatment variations and comparability of partici-
pants. In most cases a pooled-data analysis was not possible, thus
a descriptive summary of the results for each study was provided.
When feasible, an intention-to-treat analysis was conducted. The
number of patients in each allocated treatment group for each
outcome event was always sought, regardless of compliance and
patient ineligibility or exclusion after randomisation. If data were
unavailable in the original publication, we contacted the princi-
pal investigator of the trial to obtain additional information. If
needed, the effect of missing outcomes due to patient exclusion
after randomisation would be evaluated by means of a best- and
worst-case sensitivity analysis. Statistical analysis was performed
using the statistical tools incorporated in the software Revman
5.0.15 (Revman 2008).
R E S U L T S
Description of studies
See: Characteristics of included studies; Characteristics of
excluded studies; Characteristics of studies awaiting classification;
Characteristics of ongoing studies.
4Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
The 22 included trials compared multiple pharmacological inter-
ventions with placebo. A total of 1254 patients were included; 765
patiens took the active substance and 651 patients took placebo.
The initial search strategy resulted in 102 studies (1932 HD pa-
tients). The assessment of their eligibility based on the information
extractable from the corresponding title and abstract contents led
to the exclusion of 80 trials.The reasons were the following: open
label design (n = 31, 317/16,4% participants), reduced sample
dimension, i.e., n < 10 (n = 34, 199/10,3% participants), absence
of control (n = 5, 86/4,4% participants), , no-randomisation (n
= 3, 32 participants), case series (n = 4, 14 participants), inade-
quate blinding (n = 1, 12 participants), Jadad score < 3 (n = 1, 12
participants) and absence of clinical outcome measures (n = 1, 6
participants) (Figure 1).
TRIAL DESIGN:
Nine trials had a cross-over design (Consroe P; De Roover J; Goetz
CG ; Mateo D; Murman DL; O’Suilleabhain P; Quinn N; Roos
RA; Verhagen Metman L) and 13 had a parallel design (Como
PG; Cubo E; Hersch G; INTRO-HD; Kieburtz K; Miraxion-
Europe; MINO; RID-HD; Stocchi F; TETRA-HD; TREND-
5Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
HD; Vaddadi K; van Vugt J). In five cross-over trials there was
a wash-out period between active and placebo periods (Consroe
P; Goetz CG; Mateo D; Murman DL; Quinn N). In one of the
cross-over trials without washout period (De Roover J), the carry-
over effect or the influence of period sequence was not calculated.
In two other trials, a pharmacokinetic reason was given for not
incorporating a washout period (Stocchi F; Verhagen Metman L).
This was judged acceptable by the reviewers.
Fourteen trials were conducted in a single centre and eight trials
were multicentric (Como PG; Hersch G; INTRO-HD; MINO;
Miraxion-Europe; RID-HD; TETRA-HD; TREND-HD). Study
duration ranged between 2 weeks and 80 weeks (average: 10.0 ±
7.4 weeks). Trials were published between 1982 and 2007, all of
them in English, with the exception of one written in Spanish (
Mateo D).
PARTICIPANTS:
The mean age of patients was 48.4 years, ranging from 43.6 to 53.0
years of age across 19 of the included trials. The age of patients
was not available in three trials (Miraxion-Europe; TREND-HD;
Verhagen Metman L). Included patients had a mean of disease
duration of 6.3 years, ranging from 2.3 to 9.6 years. Disease du-
ration was not available in five trials (Miraxion-Europe; Roos RA;
TREND-HD; Vaddadi K; Verhagen Metman L).
INTERVENTIONS:
The following pharmacological interventions were found: Aman-
tadine (O’Suilleabhain P; Verhagen Metman L), Cannabidiol
(Consroe P), Clozapine (van Vugt J), creatine (Hersch G),
Donepezil (Cubo E), ethyl-eicosapentaenoic acid (Miraxion-
Europe; TREND-HD), Fluoxetine (Como PG), Ketamine (
Murman DL), L-acetyl carnitine (Goetz CG), Minocycline (
MINO), OPC-14117 (INTRO-HD), Piracetam (Mateo D),
Remacemide (Kieburtz K), Riluzole (RID-HD), Sulpiride (Quinn
N), Tetrabenazine (TETRA-HD), Tiapride (Roos RA; De Roover
J), Trans-dihydrolisuride (Stocchi F) and unsaturated fatty acids (
Vaddadi K).
OUTCOME MEASURES:
In eight trials the primary outcome measure was defined as the con-
trol of a motor symptom, specifically, chorea using the UHDRS
motor scale (Cubo E; RID-HD; TETRA-HD; Verhagen Metman
L), the Marsden and Quinn scale (Consroe P) or a 24-point scale
for which the inter-rater validity was assessed (O’Suilleabhain P).
A reduced form of the Total Motor Score-UHDRS (TMS-4) was
also used (Miraxion-Europe; TREND-HD). In one trial the pri-
mary outcome measure was the improvement of cognitive func-
tion measured using a cognitive testing battery (Murman DL).
Functional capacity (TFC-UHDRS) was used in one study (Como
PG). Another primary outcome measure was safety and/or toler-
ability (Hersch G; INTRO-HD; Kieburtz K; MINO). The pri-
mary outcome measure was not clearly stated in eight trials (De
Roover J; Goetz CG; Mateo D; Quinn N; Roos RA; Stocchi F;
Vaddadi K; van Vugt J).
Risk of bias in included studies
RANDOMISATION:
In eight trials, the description of the randomisation methodology
was incorporated in the original publication. Specifically, com-
puter generated 2:1 unbalanced design (TETRA-HD), a random
number table with blocking (Verhagen Metman L), computer gen-
erated blocking and stratification (Como PG; Hersch G; MINO;
RID-HD) and computer generated blocking (Miraxion-Europe;
TREND-HD). In the remaining trials only a reference to ran-
domisation was identifiable; descriptions of the adopted method-
ology were absent.
ALLOCATION CONCEALMENT:
Allocation was described and found to be adequately concealed
in seven trials (Miraxion-Europe; O’Suilleabhain P; RID-HD;
TETRA-HD; TREND-HD; Vaddadi K;van Vugt J). In the re-
maining trials, allocation concealment was not described (Como
PG; Consroe P; Cubo E; De Roover J; Goetz CG; Kieburtz K;
Hersch G; INTRO-HD; Mateo D; MINO; Murman DL; Quinn
N; Roos RA; Stocchi F; Verhagen Metman L). The authors de-
cided to include these trials in the present review.
SAMPLE SIZE CALCULATION:
Sample size calculation was conducted in 13 trials (Consroe P;
Cubo E; Kieburtz K; Hersch G; INTRO-HD; MINO; Miraxion-
Europe; O’Suilleabhain P; Quinn N; RID-HD; TETRA-HD;
TREND-HD; Verhagen Metman L).
DATA INCLUDED:
Ten trials analysed their results on a intention-to-treat basis (Goetz
CG; Hersch G; INTRO-HD; Kieburtz K; Mateo D; MINO;
RID-HD; Roos RA; Stocchi F; TETRA-HD); eleven trials con-
ducted data analysis on a per-protocol basis (Como PG; Consroe P;
Cubo E; De Roover J; Miraxion-Europe; O’Suilleabhain P; Quinn
N; TREND-HD; Vaddadi K; van Vugt J; Verhagen Metman L).
It was not possible to determine the adopted approach in one trial
(Murman DL).
Effects of interventions
Results are expressed as mean ± standard deviation, unless other-
wise indicated.
Anti-dopaminergic. Five trials were selected (De Roover J; Quinn
N; Roos RA; TETRA-HD; van Vugt J).
6Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
The trial (n = 84) using the monoamine-depleting agent Tetra-
benazine with a dose of 100 mg/day (TETRA-HD) reported a
decrease in total maximal chorea using the UHDRS motor scale (-
5.0 ± 0.5 treatment group vs. -1.5 ± 0.7 placebo group; p < 0.0001)
with an estimated treatment effect of a 3.5 point reduction (95
% CI: -5.2; -1.9, p < 0.0001) in the chorea score (min: 0 ; max:
28) independent of age, gender, trinucleotide repeat length, gen-
der of affected parent, baseline Clinical Global Impression (CGI)
severity or baseline chorea score. A corresponding improvement
in the CGI scale favouring treatment was also observed: 3.0 ± 0.2
treatment group vs. 3.7 ± 0.2 placebo group; p < 0.007. However,
Tetrabenazine proved to be deleterious in a statistically significant
fashion for a few exploratory outcome measures, namely, the UH-
DRS Functional Checklist (-0.8 ± 0.3 treatment group vs. 0.4 ±
0.4 placebo group; p = 0.02), the 17-item Hamilton Depression
scale (-0.7 ± 0.3 treatment group vs. -2.4 ± 0.4 placebo group;
p = 0.003), the Epworth Sleepiness Scale (1.5 ± 0.5 treatment
group vs. -0.3 ± 0.6 placebo group; p = 0.02), and the Stroop-
word reading test (-4.8 ± 1.5 treatment group vs. 1.8 ± 2.1 placebo
group; p = 0.01). Tetrabenazine was not different from placebo in
the Barnes Akathisia Rating Scale nor in the remaining items of
the UHDRS scale (Total Functional Capacity, Independence and
Behavioural scales, Stroop colour naming and interference tests,
and swallowing, speech and gait items of motor scale). The ex-
clusive occurrence of drop-outs in the treatment group (9.2 % of
treated patients, n = 5) was also relevant. Those were due to ad-
verse events (akathisia, suicide, intracranial haemorrhage, depres-
sion/restlessness and breast cancer).
For the drug Sulpiride, the trial of Quinn and Marsden (Quinn
N) evaluated 11 patients taking 300-1200 mg of Sulpiride/day
(mean dosage: 1054 mg/day). A positive result was found for the
median movement count (38 during placebo phase vs. 14 during
treatment phase; p < 0.01) and for the median chorea severity
taking into account eight body parts (33 during placebo phase vs.
14 during treatment phase; p < 0.01). However, a corresponding
functional improvement was not observed (12 treatment group
vs. 15 placebo group; p > 0.05).
In one trial (n = 29) using Tiapride, 3 g/day (De Roover J), the au-
thors stated that Tiapride markedly improved choreic movements
in 3 out of 5 body segments (head, p = 0.00; trunk , p = 0.05; up-
per limbs, p = 0.01; lower limbs, p = 0.01) and 3 motor skills out
of 7. However, the data was presented only in a qualitative fashion
and a more descriptive statistical analysis was lacking. For the re-
maining outcome measures (wakefulness and motor performance,
anxiety, irritability, unsociability and depression) no significant
difference was found between exposure to treatment and placebo.
In the other trial with Tiapride, 300 mg/day, n = 22 (Roos RA)
the total number of choreic movements during two minutes was
not significantly different in the placebo and treatment groups if
measured using a videotape (0.02 ± 0.26 Tiapride-placebo group
vs. -0.26 ± 0.66 placebo-Tiapride group; p = 0.20) or a whole-
body Doppler radar (0.19 ± 0.49 Tiapride-placebo group vs. -0.36
± 0.91 placebo-Tiapride group; p = 0.10).
In the trial assessing Clozapine (n = 33) on a maximum dosage
of 150 mg/day (van Vugt J) a reduction in the grade of chorea (-
7.3 ± 3.4 treatment group vs. 0 ± 4.8 placebo group; p = 0.02 )
in the cohort of neuroleptic-naive patients (n = 18) was reported.
By contrast, no significant reduction in chorea was found in the
same group when using the UHDRS scale (-4.0 ± 3.0 treatment
group vs. -0.3 ± 3.7 placebo group; p = 0.07) and patients on
Clozapine scored worse on a self-evaluated disability scale (5.7
± 9.2 treatment group vs. -3.8 ± 7.7 placebo group; p = 0.02 ).
Accordingly, the authors also stated that anti-choreic effects were
more evident with higher doses of Clozapine, simultaneously with
a higher incidence of adverse effects. No statistically significant
results were observed in the neuroleptic-treated patients group (n
= 8). Results of the whole cohort were not available for analysis.
Anti-glutamatergic. Two trials were found to study Amantadine
(O’Suilleabhain P; Verhagen Metman L) and one trial studied
Riluzole (RID-HD). Phase II trials testing Remacemide (Kieburtz
K) and Ketamine (Murman DL) were also selected. Regarding
Amantadine, one trial (Verhagen Metman L) (mean dosage: 386
mg/day in the range 100-400 mg, n = 24) reported efficacy for
Amantadine in reducing median maximal chorea (18 %; range: -
40 % to 68 % treatment period vs. 5 %, range: -100 % to 41.5
% placebo period; p = 0.0007) and median rest chorea (25 %;
range: -150 % to 100 % treatment period vs. 5 %; range: -150 %
to 71.4 % placebo period; p = 0.013). A wide variation of Aman-
tadine concentration was suggested to explain the wide range of
variability in Amantadine anti-choreic effects. In the other selected
trial testing Amantadine (O’Suilleabhain P) at a daily dose of 300
mg/day in 25 patients, the change in mean chorea score was not
significantly different between groups (difference between Aman-
tadine and placebo: 95 % CI: -1.43 to 1.0). The same was observed
for proprioceptive tasks. However, in a semi-quantitative patient
questionnaire a higher number of patients reported a subjective
benefit on chorea (19 subjects treatment period vs. 6 placebo pe-
riod; p = 0.006) and quality of life (3.9 ± 0.7 treatment period
vs. -2.95 ± 0.7 placebo period; p < 0.001). A meta-analysis was
conducted. The results were expressed as percentage relative to
the maximum score of the used scales. The pooled result does not
significantly favour treatment with Amantadine for the control of
chorea: the standardised mean difference for reduction of chorea
intensity was -0.25 % (95 % CI -0.93, 0.43) (Figure 2).
7Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 2. Forest plot of comparison: Amantadine. Change in maximal chorea (%) [extrapolated SD (r=0.5)].
8Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
In a trial with Riluzole (n = 63) (RID-HD), 100 or 200 mg/day,
200 mg/day of Riluzole showed efficacy for the selected primary
outcome measure (change in total chorea score-UHDRS: -2.2 ±
3.3 Riluzole 200 mg vs. 0.7 ± 3.4 placebo group; p = 0.01) al-
though the post hoc analysis evidenced the absence of significance
when neuroleptic-treated patients were removed from analysis.
The secondary outcome measure (change in TMS-UHDRS) was
significantly different between groups (-4.0 ± 7.1 Riluzole 200 mg
vs. 1.6 ± 7.4 placebo group; p = 0.03); a contribution of chorea
reduction for the latter was put forward by the authors as a puta-
tive explanation. Other items of the UHDRS defined as secondary
efficacy outcome measures (change in total dystonia score, Stroop
interference test, independence scale) were not significantly dif-
ferent between treatment and placebo groups. A safety issue was
raised due to a persistent and significant elevation of hepatic liver
enzymes in the Riluzole group (8 cases in the group of Riluzole
100 mg/day, and 14 cases in the group of Riluzole 200 mg/day),
which curtailed further investigation with Riluzole in a dose of
200 mg/day.
In a trial with Ketamine (n = 10) (Murman DL), 0.1, 0.4 and
0.6 mg/kg/hr, the clinical effect of NMDA blockade was studied
by using increasing doses of the drug. The intermediate dose (0.4
mg/kg/hr) produced a decline in verbal and fluency memory items
(immediate recall in Buschke Selective Reminding Test -4.4 ± 0.7
treatment period vs. -6.9 ± 0.2 placebo period; p < 0.05, immediate
and delayed recall in the Washington Square Picture Memory test
and in verbal fluency test -6.2 ± 2.1 treatment period vs. 9.1 ± 1.6
placebo period; p < 0.05). Higher doses (0.6 mg/kg/hr) produced
behavioural symptoms (increase in the Brief Psychiatric Rating
Scale total score (50.4 ± 5.7 treatment period vs. 27.1 ± 1.3 placebo
period; p < 0.05), anergia (3.0 ± 0.5 treatment period vs. 1.1
± 0.0 placebo period; p < 0.05), thought disorders (1.8 ± 0.3
treatment period vs. 1.1 ± 0.0 placebo period; p < 0.05) and
an increase in the Institute of Mental Health’s Self Rating Scale
total score as well as in its items of functional deficit and altered
self-awareness. Deteriorations in the total motor score (21.0 ± 4.1
treatment period vs. 13.3 ± 3.0 placebo period; p < 0.05) and
eye movements (8.1 ± 2.5 treatment period vs. 3.9 ± 1.4 placebo
period; p < 0.05) measured by the UHDRS were observed.
The trial studying Remacemide 200 or 600 mg/day (n = 31) (
Kieburtz K) produced negative results. A beneficial trend was re-
ported for maximal chorea grade using Huntington Disease Mo-
tor Rating Scale (HDMRS) (1.6 ± 3.7 Remacemide 200 mg vs.
1.1 ± 2.4 placebo group; p < 0.15), for three immediate-recall
trials of Hopkins Verbal Learning Test (1.4 ± 2.0 (trial 1) and
0.9 ± 1.3 (trial 2) Remacemide 200 mg vs. 0.2 ± 1.3 (trial 1)
and 0.5 ± 1.0 (trial 2) placebo group; p < 0.10), and the Stroop
colour naming test (0.04 ± 0.14 Remacemide 200 mg vs. 0.07 ±
0.13 placebo group; p < 0.17). Other assessments of frontal lobe
function, depression and functional capacity using the Hunting-
ton Disease Functional Capacity Scale (HDFCS) produced non-
significant difference between groups.
Energy metabolite.
Trials with ethyl-eicosapentaenoic acid (Miraxion-Europe;
TREND-HD) and with unsaturated fatty acids (Vaddadi K) were
included. Phase II trials of L-acetyl carnitine (Goetz CG) and cre-
atine (Hersch G) were also selected. Globally, only the trial assess-
ing the use of unsaturated fatty acids (8 g/day, n = 19)(Vaddadi
K ) reported positive results. Specifically, a reduction in dyskine-
sia measured by the Rockland-Simpson Dyskinesia Rating scale
(RSDS): -4.3 ± 2.1 treatment group vs. 7.0 ± 3.7 placebo group; p
= 0.01. Nevertheless, the latter was not considered a primary out-
come measure. No treatment effect was reported in the remain-
ing efficacy outcome measures: change in TMS-UHDRS: -3.4 ±
4.0 treatment group vs. 10.3 ± 4.7 placebo group, p = 0.08, and
change in combined UHDRS functional and cognitive scores: -
1.3 ± 2.0 treatment group vs. 5.4 ± 2.1 placebo group, p = 0.08.
In the two trials studying ethyl-eicosapentaenoic acid, 2 g/day, n
= 290 (Miraxion-Europe) and n = 316 (TREND-HD) no signifi-
cant effect was observed for the primary efficacy outcome measure,
i.e., the effect on motor phenotype as measured by the reduced
version of the total motor score of UHDRS (TMS-4). Regarding
the TREND-HD trial, a 0.2 point worsening in treatment group
vs. 1.0 point worsening in placebo group (p = 0.21) was observed
using the same scale. In the sub-group analysis (CAG repeat<45)
the TMS-4 was also not different between the ethyl-eicosapen-
taenoic acid group (0.0 point) and the placebo group (0.3 point;
p = 0.68).
In the trial of Goetz CG (n = 10) the acute effect of L-acetyl carni-
tine, 45 mg/kg/day, was studied. Measures of disability (Shoulson-
Fahn Disability scale), abnormal movements (Abnormal Invol-
untary Movements Scale and reaction time), dementia (MMSE,
Controlled Oral World association) and depression (Hamilton
Depression scale) were not significantly different in placebo and
treatment groups.
In the creatine trial (Hersch G), 8 mg/day, n = 64, in all the selected
secondary efficacy outcome measures there was no difference be-
tween placebo and treatment groups. Those outcome measures
comprehended sub-items of UHDRS scale such as total chorea
score, total motor score, verbal fluency test, symbol digit test, and
Stroop interference test. No statistical significance was presented.
Free-radical scavenger. In a phase II trial testing OPC-14117, 60-
120-240 mg/day, n = 64 (INTRO-HD), no difference was found
between treatment and placebo groups on the defined efficacy
outcome measures (change in total score of UHDRS and its sub-
items, executive function measured by neuropsychological tests
and depression measured by the Beck Depression Inventory).
Others.Trials with Cannabidiol (Consroe P), Donepezil (Cubo
E), Fluoxetine (Como PG), Minocycline (MINO), Piracetam (
Mateo D), and trans-dyhidrolisuride (Stocchi F) were included.
All trials were negative for efficacy outcome measures.
In the trial of Consroe P, Cannabidiol 10 mg/kg/day, n = 18, non-
significant changes were obtained in chorea severity (Marsden and
9Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Quinn scale; 11.2 ± 1.4 placebo period vs. 11.4 ± 1.4 treatment
period; p = 0.71) and in functional capacity (Shoulson and Fahn
functional disability scale; 6.7 ± 0.6 placebo period vs. 6.9 ± 0.5
treatment period; p = 0.14)and HD staging system; 2.9 ± 0.1
placebo period vs. 3.0 ± 0.1 treatment period; p = 0.18). In a
variety of other tests measuring motor function, cognition and
psychological distress (SLC-90R) no difference was found between
treatment and placebo periods.
In the trial of Cubo E, Donepezil (10 mg/day, n = 30) no signif-
icant improvement was observed for the primary outcome. i.e.,
chorea, using the UHDRS. Similar results were observed for the
selected secondary outcomes, i.e., total motor score of UHDRS,
bradykinesia (UHDRS) and measures of cognition and quality of
life (modified Sickness Impact Profile). Nevertheless, the authors
reported a trend in favour of d for the UHDRS functional check-
list: median [range], 0 [-5 to 3] placebo group vs. 0.5 [0 to 3]
treatment group, p = 0.051.
For the Fluoxetine trial (Como PG), Fluoxetine 20 mg/day, n =
30, the outcome functional capacity (TFC-UHDRS) was not sta-
tistically different between groups (0.09 ± 2.0 placebo group vs.
0.25 ± 2.7 treatment group; p = 0,78). A similar result was ob-
tained for other motor and cognitive outcomes. Only for the item
agitation of the Cognitive Behaviour Rating Scale, a significant
different result was reported (-5.56 ± 11.7 placebo group vs. 8.73
± 12.0 treatment group; p = 0.02).
In a trial testing Piracetam (Mateo D), 12 g, n = 11, the active
substance was found to worsen involuntary movements 4 hours
after drug administration as measured by the Kartzinel, Hunt,
Calne scale.
In the trial conducted using trans-dyhidrolisuride, 5 mg/day, n
= 10 (Stocchi F), no significant results were obtained for the se-
lected outcome measures: disease severity (Marsden and Quinn
scale), involuntary movements (AIMS scale), dementia (MMSE)
and quantification of rapid wrist movements using an EMG-based
methodology.
The trial studying Minocycline (MINO),100 or 200 mg/day, n =
60, assessed the change in the TMS-UHDRS and in the cognitive
and functional components of UHDRS. A significant difference
was only observed in the Stroop interference test with the treat-
ment group performing worse: 1.87 ± 4.83 placebo group vs. 1.50
± 6.68 Minocycline 100 mg/day vs. -3.42 ± 10.5 Minocycline 200
mg/day; p = 0.04.
Adverse events and safety. With the exception of two trials (
Consroe P; Mateo D), adverse events were reported. In four-
teen trials, the occurrence or absence of serious adverse events
was reported in both treatment and control groups (Como PG;
De Roover J; Goetz CG; Kieburtz K; INTRO-HD; Mateo D;
O’Suilleabhain P; Quinn N ;RID-HD; Roos RA; Stocchi F;
TETRA-HD; van Vugt J; Verhagen Metman L). In four of those
trials, serious adverse events were observed exclusively in the treat-
ment group (INTRO-HD; RID-HD; TETRA-HD; van Vugt J).
Three trials did not provide a report of serious adverse events oc-
currence (Consroe P; Murman DL; Vaddadi K). Overall, there
were a total of 51 (6.1 %) drop-outs during inclusion in treat-
ment groups and 22 (3.4 %) drop-outs during inclusion in the
placebo groups. No drop-outs were observed in five trials (Goetz
CG; Mateo D; Murman DL; Roos RA; Stocchi F;). In 14 tri-
als, drop-outs were related to adverse events (Como PG; Cubo E;
De Roover J; Goetz CG; Kieburtz K; Hersch G; INTRO-HD;
MINO; O’Suilleabhain P; Quinn N; RID-HD; TETRA-HD;
Vaddadi K; van Vugt J) with a median per-trial frequency of 80
% (range: 0-100 %) and 58 % (range: 0-100 %) for treatment
and control groups, respectively. Concerning the trials with safety
and tolerability as primary outcomes measures, L-acetyl carnitine
was very well tolerated with no serious adverse events, or drop-
out due to adverse events (Goetz CG). Minocycline (MINO),
Remacemide (Kieburtz K) and creatine (Hersch G) were generally
well tolerated and safe. OPC-14117 (INTRO-HD) was associated
with frequent drop-outs (12.5 %; n = 8), all related to adverse
events.
D I S C U S S I O N
Regarding the symptomatic control of HD, the present review
shows that anti-dopaminergic agents, glutamate antagonists and
one energy metabolite seem to have a positive effect for motor
symptoms. Trials with Tetrabenazine (TETRA-HD), amantadine
(Verhagen Metman L), Riluzole (RID-HD) and unsaturated fatty
acids (Vaddadi K) used validated scales, namely, the UHDRS mo-
tor scale (RID-HD; TETRA-HD; Verhagen Metman L) and the
RSDRS (Vaddadi K). The remaining trials testing medications be-
longing to the same pharmacological classes were negative and/or
presented serious methodological constraints. In the trial with
clozapine (van Vugt J) results from the original cohort were not
available and the putative anti-choreic effect of Clozapine was not
consistent across the two scales used for that purpose, i.e. AIMS,
and UHDRS-chorea score. In the trial by De Roover J method-
ological issues were also raised: this was a cross-over study but no
washout between treatment and placebo periods was adopted, and
the carry-over effect was not calculated. The trial with Sulpiride (
Quinn N) did not use a validated scale.
In the aforementioned trials reporting significant positive results,
the Tetrabenazine trial (TETRA-HD) presented less methodolog-
ical flaws, used a larger patient sample and was able to show a
more robust anti-choreic effect than the other trials. Nevertheless,
Tetrabenazine-treated patients performed worse in functional out-
come measures and serious adverse events occurred exclusively in
the treatment group. These aspects should be weighed in the as-
sessment of its overall effectiveness and when using Tetrabenazine
in the clinical management of chorea in HD patients. Regarding
Amantadine, although one trial reported positive results (Verhagen
Metman L), the other selected trial (O’Suilleabhain P) with a simi-
10Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
lar cross-over design rendered opposite results. The pool-data anal-
ysis demonstrated the existence of a non-significant anti-choreic
effect. As for Riluzole, its efficacy was only demonstrated in the
200 mg/day group, a dosage associated with an excess of hepatic
toxicity, which advises against its clinical use at that daily dose.
Recently, a trial using similar outcome measures but with disease-
modifying objectives unequivocally demonstrated the lack of effi-
cacy of Riluzole 100 mg/day for the treatment of HD patients (
EHDN 2007). Regarding unsaturated fatty acids, the anti-dyski-
netic effect reported by the authors must be put into perspective
with more recent trials (Miraxion-Europe; TREND-HD) showing
that ethyl-eicosapentaenoic acid was not effective in the control of
chorea and other motor symptoms. Ethyl-eicosapentaenoic acid
was one of the unsaturated fatty acids mixtures used by Vaddadi
K .
Finally, the analysis of the used outcome measures shows that non-
motor symptoms have not been specifically addressed in HD in-
terventional studies. In fact, none of the selected trials was primar-
ily conducted to study therapeutic effects on the control of psy-
chiatric symptoms or cognitive decline, which have a significant
effect on the quality of life of the patient with HD and his/her
next of kin or caregiver.
A U T H O R S ’ C O N C L U S I O N SImplications for practice
No intervention has proven to have a consistent symptomatic con-
trol in HD. The current review regards Tetrabenazine as the anti-
choreic medication with best available clinical evidence. Never-
theless, only one trial has been included in the present systematic
review. No statement can be made regarding the effectiveness of
available medication in other areas of symptomatic control due to
the lack of evidence extractable from clinical trials.
No statement can be made regarding the best medical practice for
the control of motor and non-motor symptoms in HD.
Implications for research
Further double-blind, randomised, placebo-controlled trials ade-
quately powered must be conducted to study the effectiveness of
therapeutic interventions for the symptomatic control of HD, not
only for motor symptoms but also for other symptomatic areas.
The efficacy of therapeutic interventions previously shown to be
safe in the symptomatic treatment of HD should be studied by
conducting properly sampled clinical trials.
A C K N O W L E D G E M E N T S
We thank Dr. Padraig O’Suilheabhain, Dr. Leo Verhagen-Met-
man, Dr. Jeroen van Vugt and Professor Raymond Roos for sup-
plying original unpublished data. We also thank Dr. Frederick
Marshal and Professor Krishna Vaddadi for answering our ques-
tions regarding methodological issues of related trials.
R E F E R E N C E S
References to studies included in this review
Como PG {published data only}
Como PG, Rubin AJ, O’Brien CF, Lawler K, Hickey C, Rubin AE,
et al.A controlled trial of fluoxetine in nondepressed patients with
Huntington’s disease. Mov Disord 1997;12(3):397-401 1997;12(3):
397–401.
Consroe P {published data only}
Consroe P, Laguna J, Allender J, Snider S, Stern L, Sandyk R, et
al.Controlled clinical trial of cannabidiol in Huntington’s disease.
Pharmacol Biochem Behav 1991;40(3):701–8.
Cubo E {published data only}∗ Cubo E, Shannon KM, Tracy D, Jaglin JA, Bernard BA, Wuu
J, Leurgans SE. Effect of donepezil on motor and cognitive func-
tion in Huntington disease. Neurology 2006;10(7):1268–71. [DOI:
10.1212/01.wnl.0000238106.10423.00]
De Roover J {published and unpublished data}
Deroover J, Baro F, Bourguignon RP, Smets P. Tiapride versus
placebo: a double-blind comparative study in the management of
Huntington’s chorea. Curr Med Res Opin 1984;9(5):329–38.
Goetz CG {published data only}
Goetz CG, Tanner CM, Cohen JA, Thelen JA, Carroll VS, Klawans
HL, et al.L-acetyl-carnitine in Huntington’s disease: double-blind
placebo controlled crossover study of drug effects on movement dis-
order and dementia. Mov Disord 1990;5(3):263–5.
Hersch G {published data only}
Hersch SM, Gevorkian S, Marder K, Moskowitz C, Feigin A, Cox M,
et al.Creatine in Huntington disease is safe, tolerable, bioavailable in
brain and reduces serum 8OH2’dG. Neurology 2006;66(2):250–2.
INTRO-HD {published data only}
The Huntington Study Group. Safety and tolerability of the free-
radical scavenger OPC-14117 in Huntington’s disease.. Neurology
1998;50:1366–1372.
Kieburtz K {published data only}
Kieburtz K, Feigin A, McDermott M, Como P, Abwender D, Zim-
merman C, et al.A controlled trial of remacemide hydrochloride in
Huntington’s disease. Mov Disord 1996;11(3):273–7.
Mateo D {published and unpublished data}
Mateo D, Gimenez-Roldan S. The effect of piracetam on involun-
tary movements in Huntington’s disease. A double-blind, placebo-
controlled study [El efecto del piracetam en los movimientos invol-
11Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
untarios en la enfermedad de Huntington]. Neurologia 1996;11(1):
16–9.
MINO {published data only}
The Huntington study group. Minocycline safety and tolerability in
Huntington disease. Neurology 2004;63(3):547–9.
Miraxion-Europe {unpublished data only}
World Congress in Huntington´ s disease. 2007.
Murman DL {published data only}
Murman DL, Giordani B, Mellow AM, Johanns JR, Little RJ, Hari-
haran M, et al.Cognitive, behavioral, and motor effects of the NMDA
antagonist ketamine in Huntington’s disease. Neurology 1997;49(1):
153–61.
O’Suilleabhain P {published and unpublished data}
O’Suilleabhain P, Dewey RB, Jr. A randomized trial of amantadine
in Huntington disease. Arch Neurol 2003;60(7):996–8.
Quinn N {published data only}
Quinn N, Marsden CD. A double blind trial of sulpiride in Hunt-
ington’s disease and tardive dyskinesia. J Neurol Neurosurg Psychiatry
1984;47(8):844–7.
RID-HD {published data only}
The Huntington study group. Dosage effects of riluzole in Hunt-
ington’s disease: a multicenter placebo-controlled study. Neurology
2003;61(11):1551–6..
Roos RA {published and unpublished data}
Roos RA, Buruma OJ, Bruyn GW, Kemp B, van der Velde EA.
Tiapride in the treatment of Huntington’s chorea. Acta Neurol Scand
1982;65(1):45–50.
Stocchi F {published data only}
Stocchi F, Carta A, Berardelli A, Antonini A, Argenta M, Formica A,
et al.Effects of terguride in patients with Huntington’s disease. Clin
Neuropharmacol 1989;12(5):435–9.
TETRA-HD {published and unpublished data}
The Huntington study group. Tetrabenazine as antichorea therapy in
Huntington disease: a randomized controlled trial. Neurology 2006;
66(3):366–72.
TREND-HD {published data only}
The Huntington Study group. TREND-HD - A Trial of Ethyl-EPA
(Miraxion™) in Treating Mild to Moderate Huntington’s Disease.
World Congress in Huntington´ s disease. 2007.
Vaddadi K {published and unpublished data}
Vaddadi KS, Soosai E, Chiu E, Dingjan P. A randomised, placebo-
controlled, double blind study of treatment of Huntington’s disease
with unsaturated fatty acids. Neuroreport 2002;13(1):29–33.
van Vugt J {published and unpublished data}
van Vugt JP, Siesling S, Vergeer M, van der Velde EA, Roos RA.
Clozapine versus placebo in Huntington’s disease: a double blind
randomised comparative study. J Neurol Neurosurg Psychiatry 1997;
63(1):35–9.
Verhagen Metman L {published and unpublished data}
Verhagen Metman L, Morris MJ, Farmer C, Gillespie M, Mosby K,
Wuu J, et al 12. Huntington’s disease: a randomized, controlled
trial using the NMDA-antagonist amantadine. Neurology 2002;59
(5):694–92.
References to studies excluded from this review
Albanese A {published data only}
Albanese A, Cassetta E, Carretta D, Bentivoglio AR, Tonali P. Acute
challenge with apomorphine in Huntington’s disease: a double-blind
study. Clin Neuropharmacol 1995;18(5):427–34.
Albano C {published data only}
Albano C, Cocito L. Huntington’s chorea and bromocriptine. Arch
Neurol 1979;36(5):322.
Alpay M {published data only}
Alpay M, Koroshetz WJ. Quetiapine in the treatment of behavioral
disturbances in patients with Huntington’s disease. Psychosomatics
2006;47(1):70–2.
Aminoff MJ {published data only}
Aminoff MJ, Marshall J. Treatment of Huntington’s chorea with
lithium carbonate. A double-blind trial. Lancet 1974;1(7848):107–
9.
Asher SW {published data only}
Asher SW, Aminoff MJ. Tetrabenazine and movement disorders.
Neurology 1981;31(8):1051–4.
Barr AN {published data only}
Barr AN, Heinze W, Mendoza JE, Perlik S. Long term treatment
of Huntington disease with L-glutamate and pyridoxine. Neurology
1978;28(12):1280–2.
Bassi S (a) {published data only}
Bassi S, Albizzati MG, Corsini GU, Frattola L, Piolti R, Suchy I,
Trabucchi M. Therapeutic experience with transdihydrolisuride in
Huntington’s disease. Neurology 1986;36(7):984–6.
Bonelli RM {published data only}
Bonelli RM, Mahnert FA, Niederwieser G. Olanzapine for Hunt-
ington’s disease: an open label study. Clin Neuropharmacol 2002;25
(5):263–5.
Bonuccelli U {published data only}
Bonuccelli U, Ceravolo R, Maremmani C, Nuti A, Rossi G, Mura-
torio A. Clozapine in Huntington’s chorea. Neurology 1994;44(5):
821–3.
Braun A {published data only}
Braun A, Mouradian MM, Mohr E, Fabbrini G, Chase TN. Selective
D-1 dopamine receptor agonist effects in hyperkinetic extrapyrami-
dal disorders. J Neurol Neurosurg Psychiatry 1989;52(5):631–5.
Caine ED {published data only}
Caine ED, Polinsky RJ, Kartzinel R, Ebert MH. The trial use of
clozapine for abnormal involuntary movement disorders. Am J Psy-
chiatry 1979;136(3):317–20.
Caparros-Lefebvre D {published data only}
Caparros-Lefebvre D, Dewailly D. [Preliminary pilot study of cypro-
terone acetate for the treatment of aggressive behavior associated with
severe dementia]. Rev Neurol (Paris) 2005;161(11):1071–8.
Caraceni TA (a) {published data only}
Caraceni TA, Giovannini P, Girotti F, Avanzini G. Pharmacology of
Huntington´ s disease. Personal experience. Eur Neurol 1977;16(1-
6):42–50.
Caraceni TA (b) {published data only}
Caraceni TA, Girotti F, Celano I, Parati E, Balboni L. 2-Dymethy-
laminoethanol (Deanol) in Huntington´ s chorea. Journal of Neurol-
ogy, Neurosurgery and Psychiatry 1978;41:1114–1118.
12Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Caraceni TA (c) {published data only}
Caraceni TA, Girotti F, Giovannini P, Pederzoli M, Parati EA. Effects
of DA agonist in Huntington disease hyperkinesia. Ital J Neurol Sci
1980;1(3):155–161.
Carman JS {published data only}
Carman JS, Shoulson I, Chase TN. Huntington´ s chorea treated
with lithium carbonate. The Lancet 1974;1(7861):811.
Corsini GU {published data only}
Corsini GU, Onali P, Masala C, Cianchetti C, Mangoni A, Gessa G.
Apomorphine hydrochloride-induced improvement in Huntington’s
chorea: stimulation of dopamine receptor. Arch Neurol 1978;35(1):
27–30.
Dalby M {published data only}
Dalby MA. Effect of tetrabenazine on extrapyramidal movement dis-
orders. Br Med J 1969;2(5654):422–423.
Dallochio C {published data only}
Dallocchio C, Buffa C, Tinelli C, Mazzarello P. Effectiveness of
risperidone in Huntington chorea patients. J Clin Psychopharmacol
1999;19(1):101–3.
de Tommaso (a) {published data only}
de Tommaso M, Specchio N, Sciruicchio V, Difruscolo O, Specchio
LM. Effects of rivastigmine on motor and cognitive impairment in
Huntington’s disease. Mov Disord 2004;19(12):1516–1518.
de Tommaso (b) {published data only}
de Tommaso M, Di Fruscolo O, Sciruicchio V, Specchio N, Cormio
C, De Caro MF, Livrea P. Efficacy of levetiracetam in Huntington
disease. Clin. Neuropharmacol 2005;28(6):280–4.
de Tommaso (c) {published data only}
de Tommaso M, Difruscolo O, Sciruicchio V, Specchio N, Livrea
P. Two years’ follow-up of rivastigmine treatment in Huntington
Disease. Clinical Neuropharmacology 2007;30(1):43–46.
Destée A {published data only}
Destée A, Petit H, Warot P. Effect of piracetam in Huntington’s
chorea. Eur Neurol 1984;23(2):89–91.
Dupont E {published data only}
Dupont E, Hansen AP, Juul-Jensen P, Lundbaek K, Magnussen I,
de Fine Olivarius B. Somatostatin in the treatment of patients with
extra-pyramidal disorders and patients with EEG abnormalities. Acta
Neurol Scand 1978;57(6):488–93.
Fernandez HH {published data only}
Fernandez HH, Friedman JH, Grace J, Beason-Hazen S. Donepezil
for Huntington’s disease. Mov Disord 2000;15(1):173–6.
Fisher R (a) {published data only}
Fisher R, Norris JW, Gilka L. Letter: G.A.B.A. in Huntington´ s
chorea. Lancet 1974;1(7856):506.
Fisher R (b) {published data only}
Fisher R, Norris W, DeManuele F, Ridgley B, Malyon C.
Huntington´ s chorea. Can Med Assoc J 1982;126(6):605–606.
Fog R {published data only}
Fog R, Pakkenberg H. Combined nitoman-pimozide treatment of
Huntington’s chorea and other hyperkinetic syndromes. Acta Neurol
Scand. 1970;46(2):249–51.
Foster NL {published data only}
Foster NL, Chase TN, Denaro A, Hare TA, Tamminga CA. THIP
treatment of Huntington’s disease. Neurology 1983;33(5):637–9.
Frattola L (a) {published data only}
Frattola L, Albizzati MG, Alemani A, Bassi S, Ferrarese C, Trabucchi
M. Acute treatment of Huntington’s chorea with lisuride. J Neurol
Sci 1983;59(2):247–53.
Frattola L (b) {published data only}
Frattola L, Albizzati MG, Alemani A, Bassi S, Ferrarese C, Trabucchi
M. Acute treatment of Huntington’s chorea with lisuride. J Neurol
Sci 1983;59(2):247–53.
Giménez-Roldán S {published data only}
Giménez-Roldán S, Mateo D. [Huntington disease: tetrabenazine
compared to haloperidol in the reduction of involuntary move-
ments]. Neurologia 1989;4(8):282–7.
Girke W {published data only}
Girke W, Lieske V. [Influence of the Benzodiazepine-derivative
Ro 06-9098/000 on choreo-athetotic syndromes (author’s transl)].
Pharmakopsychiatr Neuropsychopharmakol 1977;10(5):281–5.
Girotti F {published data only}
Girotti F, Carella F, Scigliano G, Grassi MP, Soliveri P, Giovannini
P, Parati E, Caraceni T. Effect of neuroleptic treatment on involun-
tary movements and motor performances in Huntington’s disease. J
Neurol Neurosurg Psychiatry 1984;47(8):848–852.
Giuffra ME {published data only}
Giuffra ME, Mouradian MM, Chase TN. Glutamatergic therapy of
Huntington’s chorea. Clin Neuropharmacol 1992;15(2):148–151.
Gray MW {published data only}
Gray MW, Herzberg L, Lerman JA, Turnbull MJ, Victoratos G. Let-
ter: Amantadine in chorea. Lancet 1975;2(7925):132–133.
Haslam MT {published data only}
Haslam MT. Cellular magnesium levels and the use of penicillamine
in the treatment of Huntington’s chorea. J Neurol Neurosurg Psychi-
atry 1967;30(2):185–8.
Heckman JM {published data only}
Heckmann JM, Legg P, Sklar D, Fine J, Bryer A, Kies B. IV amanta-
dine improves chorea in Huntington’s disease: an acute randomized,
controlled study. Neurology 2004;63(3):597–8.
Jankovic J {published data only}
Jankovic J. Treatment of hyperkinetic movement disorders with tetra-
benazine: a double-blind crossover study. Ann Neurol 1982;11(1):
41–7.
Kartzinel R {published data only}
Kartzinel R, Hunt RD, Calne DB. Bromocriptine in Huntington
chorea. Arch Neurol 1976;33(7):517–8.
Leng TR {published data only}
Leng TR, Woodward MJ, Stokes MJ, Swan AV, Wareing LA, Baker
R. Effects of multisensory stimulation in people with Huntington’s
disease: a randomized controlled pilot study.. Clin Rehabil 2003;17
(1):30–41.
Leonard DP {published data only}
Leonard DP, Kidson MA, Brown JG, Shannon PJ, Taryan S. A dou-
ble blind trial of lithium carbonate and haloperidol in Huntington’s
chorea. Aust N Z J Psychiatry 1975;9(2):115–8.
Lucetti C(a) {published data only}
Lucetti C, Gambaccini G, Bernardini S, Dell’Agnello G, Petrozzi L,
Rossi G, Bonuccelli U. Amantadine in Huntington’s disease: open-
label video-blinded study. Neurol Sci 2002;23(Suppl 2):S83–84.
13Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Lucetti C(b) {published data only}
Lucetti C, Del Dotto P, Gambaccini G, Dell’ Agnello G, Bernardini
S, Rossi G, Murri L, Bonuccelli U. IV amantadine improves chorea
in Huntington’s disease: an acute randomized controlled study. Neu-
rology 2003;60(12):1995–7.
Manyam BV {published data only}
Manyam BV, Katz L, Hare TA, Kaniefski K, Tremblay RD. Isoni-
azid-induced elevation of CSF GABA levels and effects on chorea in
Huntington’s disease. Ann Neurol 1981;10(1):35–7.
Mattson B {published data only}
Mattsson B, Boman K. Letter: Buronil in Huntington’s chorea.
Lancet 1974;30(2):1323.
McLellan D {published data only}
McLellan DL, Chalmers RJ, Johnson RH. A double-blind trial of
tetrabenazine, thiopropazate, and placebo in patients with chorea.
Lancet 1974;1(7848):104–7.
Nutt JG (a) {published data only}
Nutt JG, Rosin A, Chase TN. Treatment of Huntington disease with
a cholinergic agonist. Neurology 1978;28(10):1061–4.
Nutt JG (b) {published data only}
Nutt JG, Rosin AJ, Eisler T, Calne DB, Chase TN. Effect of an opiate
antagonist on movement disorders. Arch Neurol 1978;35(12):810–
811.
Ondo WG {published data only}
Ondo WG, Tintner R, Thomas M, Jankovic J. Tetrabenazine treat-
ment for Huntington’s disease-associated chorea. Clin Neurophar-
macol 2002;25(6):300–2.
Pakkenberg H {published data only}
Pakkenberg H. The effect of tetrabenazine in some hyperkinetic syn-
dromes. Acta Neurol Scand 1968;44(3):391–393.
Paleacu D {published data only}
Paleacu D, Anca M, Giladi N. Olanzapine in Huntington’s disease.
Acta Neurol Scand 2002;105(6):441–4.
Pearce I {published data only}
Pearce I, Heathfield KW, Pearce MJ. Valproate sodium in Huntington
chorea. Arch Neurol 1977;34(5):308–9.
Perry TL (a) {published data only}
Perry TL, Wright JM, Hansen S, Thomas SM, Allan BM, Baird PA,
Diewold PA. A double-blind clinical trial of isoniazid in Huntington
disease. Neurology 1982;32(4):354–8.
Perry TL (b) {published data only}
Perry TL, Wright JM, Hansen S, Allan BM, Baird PA, MacLeod
PM. Failure of aminooxyacetic acid therapy in Huntington disease.
Neurology. 1980;30(7 Pt 1):772–5.
Perry TL (c) {published data only}
Perry TL, Wright JM, Hansen S. Isoniazid therapy in Huntington
disease. Neurology 1979;29(3):370–5.
Piccinin G {published data only}
Piccinin G, Morocutti C, Urcioli R, Bernardi G. [Treatment of chor-
eic syndromes with sodium dipropylacetate]. Riv Neurol 1977;47
(2):107–16.
Saft C (a) {published data only}
Saft C, Andrich J, Kraus PH, Przuntek H. Amisulpride in Hunting-
ton’s disease. Psychiatr Prax 2005;32(7):363–66.
Saft C (b) {published data only}
Saft C, Lauter T, Kraus PH, Przuntek H, Andrich J. Dose-dependent
improvement of myoclonic hyperkinesia due to Valproic acid in eight
Huntington’s Disease patients: a case series. BMC Neurol 2006;28;
6:11.
Scigliano G {published data only}
Scigliano G, Giovannini P, Girotti F, Grassi MP, Caraceni T,
Schechter PJ. Gamma-vinyl GABA treatment of Huntington’s dis-
ease. Neurology. 1984;34(1):94–6.
Scotti G {published data only}
Scotti G, Spinnler H. Amantadine and Huntington’s chorea. N Engl
J Med 1971;285(23):1325–6.
Seppi K {published data only}
Seppi K, Mueller J, Bodner T, Brandauer E, Benke T, Weirich-
Schwaiger H, Poewe W, Wenning GK. Riluzole in Huntington’s dis-
ease (HD): an open label study with one year follow-up. J Neurol
2001 J Neurol. 2001 Oct;248(10):866–9.;248(10):866–9.
Shoulson I(a) {published data only}
Shoulson I, Chase TN, Roberts E, Van Balgooy JN. Letter: Hunt-
ington’s disease: treatment with imidazole-4-acetic acid. N Engl J
Med 1975;293(10):504–5.
Shoulson I(b) {published data only}
Shoulson I, Goldblatt D, Charlton M, Joynt RJ. Huntington’s dis-
ease: treatment with muscimol, a GABA-mimetic drug. Ann Neurol.
1978;4(3):279–84.
Shults C {published data only}
Shults C, Steardo L, Barone P, Mohr E, Juncos J, Serrati C, Fe-
dio P, Tamminga CA, Chase TN. Huntington’s disease: effect of
cysteamine, a somatostatin-depleting agent. Neurology 1986;36(8):
1099–102.
Squittieri F {published data only}
Squitieri F, Cannella M, Piorcellini A, Brusa L, Simonelli M, Rug-
gieri S. Short-term effects of olanzapine in Huntington disease. Neu-
ropsychiatry Neuropsychol Behav Neurol. 2001;14(1):69–72.
Swash M {published data only}
Swash M, Roberts AH, Zakko H, Heathfield KW. Treatment of in-
voluntary movement disorders with tetrabenazine. J Neurol Neuro-
surg Psychiatry 1972;35(2):186–91.
Symington GR {published data only}
Symington GR, Leonard DP, Shannon PJ, Vajda FJ. Sodium val-
proate in Huntington’s disease. Am J Psychiatry 1978;135(3):352–4.
Tarsy D {published data only}
Tarsy D, Bralower M. Deanol acetamidobenzoate treatment in chor-
eiform movement disorders. Arch Neurol 1977;34(12):756–8.
Tell G {published data only}
Tell G, Böhlen P, Schechter PJ, Koch-Weser J, Agid Y, Bonnet AM,
Coquillat G, Chazot G, Fischer C. Treatment of Huntington disease
with gamma-acetylenic GABA an irreversible inhibitor of GABA-
transaminase: increased CSF GABA and homocarnosine without
clinical amelioration. Neurology 1981;31(2):207–11.
Terrence CF {published data only}
Terrence CF. Fluphenazine decanoate in the treatment of chorea: a
double-blind study.Curr Ther Res Clin Exp. 1976 Aug;20(2):177-
83.. Curr Ther Res Clin Exp 1976;20(2):177–83.
14Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Tolosa ES {published data only}
Tolosa ES. Studies on the anti-dyskinesia effect of apomorphine in
man. Neurol Neurocir Psiquiatr 1976;17(4):223–9.
Tourian AY {published data only}
Tourian AY. Administration of 5-hydroxy-L-tryptophan to individ-
uals with Huntington’s chorea. Neurology 1972;22(11):1201–4.
Van Duijn E {published data only}
Van Duijn E, Roos RAC, Smarius LJCA, Van Der Mast RC. Elec-
troconvulsive therapy in patients with Huntington’s disease and de-
pression. Ned Tijdschr Geneeskd 2005;149(39):2141–44.
Vestergaard P {published data only}
Vestergaard P, Baastrup PC, Petersson H. Lithium treatment of Hunt-
ington’s chorea. A placebo-controlled clinical trial. Acta Psychiatr
Scand 1977;56(3):183–8.
Vitale P {published data only}
Vitale C, Marconi S, Di Maio L, De Michele G, Longo K, Bonavita
V, Barone P. Short-term continuous infusion of apomorphine hy-
drochloride for treatment of Huntington’s chorea: A double blind,
randomized cross-over trial. Mov. Disord 2007;22(16):2359–2364.
Walker FO {published data only}
Walker FO, Hunt VP. An open label trial of dextromethorphan in
Huntington’s disease. Clin Neuropharmacol 1989;12(4):322–30.
Worrall EP {published data only}
Worrall EP. Letter: Lithium in Huntington’s chorea. Lancet 1974;2
(7892):1323.
Zesiewicz T {published data only}
Zesiewicz, T, Sullivan KL, Hauser RA, Sanchez-Ramos J. Open-label
pilot study of levetiracetam (Keppra) for the treatment of chorea in
Huntington’s disease. Mov Disord 2006;21(11):1998–2001.
Zinzi P {published data only}
Zinzi P, Salmaso D, De Grandis R, Graziani G, Maceroni S, Ben-
tivoglio A, Zappata P, Frontali M, Jacopini G. Effects of an intensive
rehabilitation programme on patients with Huntington’s disease: A
pilot study. Clin. Rehabil 2007;21(7):603–613.
References to studies awaiting assessment
Curtis A {unpublished data only}
Curtis A. World Congress of Huntington´ s disease.
DIMOND-A {published data only}
PHEND-HD {published data only}
References to ongoing studies
Atomoxetine {published data only}
Atomoxetine for Attention Deficits in Adults With Mild HD: A
Randomised, Placebo-Controlled Crossover Study. Ongoing study
November 2005..
CIT-HD {published data only}
A randomised, placebo-controlled pilot study in Huntington’s Dis-
ease (CIT-HD).. Ongoing study November 2005..
Memantine {published data only}
A pilot study of Memantine for cognitive and behavioral dysfunction
in Huntington’s disease.. Ongoing study Starting date of trial not
provided. Contact author for more information.
Additional references
Bonneli RM 2005
Bonneli RM, Hofmann P. Pharmacological management of
Huntington´ s disease: an evidence-based review. Current Pharma-
ceutical Design 2005;12(21):2701–2720.
Cochrane 2008
www.cochrane.org/resources/handbook/.
EHDN 2007
European Huntington Disease Initiative Study Group. Riluzole in
Huntington´ s disease: a 3 year, randomised controlled study. Annals
of Neurology 2007;62(3):262–272.
HSG 1996
Huntington Study Group. Unified Huntington’s disease rating scale:
Reliability and consistency. Movement Disorders 1996;11(2):136–
42. [DOI: 10.1002/mds.870110204]
Jadad 1996
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gav-
aghan DJ, McQuay HJ. Assessing the quality of reports of random-
ized clinical trials: is blinding. Control Clin Trials 1996;17(1):1–12.
Kieburtz 1994
Kieburtz, K, et al.Trinucleotide repeat length and progression of ill-
ness in Huntington’s disease. J Med Genet 1994;31(11):872–4.
Lanska 1995
Lanska, DJ. George Huntington and hereditary chorea. J Child
Neurol 1995;10(1):46–8.
Revman 2008
Review Manager (RevMan) [MacOSX]. Version 5.0. Copenhagen:
The Nordic Cochrane Centre, The Cochrane Collaboration, 2008.
Ropper 2005
Ropper AH, Brown RH. Principles of Neurology. 8th Edition. Mc-
Graw-Hill, 2005.
TH s DCR Group 1993
Group, THsDCR. A novel gene containing a trinucleotide repeat
that is expanded and unstable on Huntington’s disease chromosome.
Cell 1993;72:971–983.∗ Indicates the major publication for the study
15Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Como PG
Methods 16-week double-blind, parallel study. Method of randomisation: computer-generated blocking and strat-
ification.
Results presented for each arm of the study.
Per-protocol data analysis.
Location: 2 centres (USA).
Participants 30 patients, 7 drop-outs. 18 male and 12 female patients.
Mean age of participants: 43.6 ±11.9 years. Mean disease duration: 6.2±4.3 years.
Inclusion criteria: HD (nondepressed and ambulatory),TFC-UHDRS between 3-13.
Exclusion criteria: antidepressant medication, Hamilton Depression Inventory≥20, MMSE≤24
Interventions Oral fluoxetine 20 mg/day (17 patients) and matching placebo (13 patients). Possible titration to fluoxetine
20 mg twice a day (not done).
Outcomes Primary: functional capacity (TFC-UHDRS).
Secondary:
• Motor signs by a standardized motor scale: (chorea, dystonia, bradykinesia, oculomotor move-
ments, cerebellar function).
• Cognitive examination (Selective Reminding test, Visual Memory test, Controlled Oral Word
Association test, Design Fluency test, Trail making test, Stroop Interference test, Digit Symbol
test, MMSE).
• Psychiatric examination (Hamilton Depression Inventory, Zung Anxiety scale, Leyton Obses-
sional Inventory, Hopkins Symptom Checklist Revised, Cognitive Behavior Rating Scale, In-
dependency scale).
Notes Negative for efficacy measures
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
16Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Consroe P
Methods 15-week double-blind, cross-over study. Washout periods: 2 weeks pre-trial and 1 week in-between blocks.
Method of randomisation: not described.
Results presented as combined data from treatment and placebo periods.
Per-protocol data analysis.
Location: 1 centre (USA).
Participants 18 patients, 3 drop-outs. 11 male and 7 female patients.
Mean age of participants: 47.8 ±15.3 years.
Mean disease duration: 5.0±2.8 years.
Inclusion criteria: HD (clinical diagnosis and positive family history), mild or moderate progression (HD
stage 1-4), cooperative, lucid and ambulatory, adequate third-party support.
Exclusion criteria: active or progressive hematologic, renal, hepatic, endocrine, cardiac or pulmonary
disease; neuroleptics (obligatory pre-trial 2 week wash-out period), child-bearing age, pregnant, fertile
women, no contraception.
Interventions Oral Cannabidiol 10 mg/kg/day. No titration.
Outcomes Primary: change in chorea severityt (Marsden and Quinn scale).
Secondary:
• Cannabis side effects (cannabis side effect inventory, blood pressure, weight, clinical laboratorial
tests, cannabidiol blood level)
• Functional capacity (Shoulson and Fahn functional disability scale and HD staging system).
• Motor and cognitive function (tongue extension test, finger tapping test, screw-and-nut test,
Buschke-Fuld selective reminding tasks).
• Psychological distress (SLC-90R).
• Physician´ s and patients´ assessment of treatment effect.
Notes Negative for efficacy measures.
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Cubo E
Methods 12-week double-blind, parallel study (follow-up: 12 weeks). Method of randomisation: random-length permuted
blocking.
Results presented for each arm of the study.
Per-protocol data analysis.
Location: 1 centre (USA).
17Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cubo E (Continued)
Participants 30 patients, 6 drop-outs. 14 male and 16 female patients.
Mean age of participants: 46.6 ± 9.8 years.
Mean disease duration: 4.7 ± 4.2 years.
Inclusion criteria: adult, positive genetic test for HD or a positive family history of chorea and psychiatric disorder,
UHDRS-chorea score minimum of 6.
Exclusion criteria: pregnancy or breastfeeding, sensitivity to donepezil, Hamilton Disease Rating scale score for de-
pression of ≥15, history of stereotaxic brain surgery for HD, use of cholinergic/anticholinergic/antidopaminergic
drugs within 4 weeks before enrollment. Dementia according to Diagnostic and Statistical Manual of Mental Disor-
ders, Fourth Edition criteria and MMSE<24.
Interventions Oral donepezil 10 mg/day (15 patients) and placebo (identical in appearance, 15 patients). Titration 5 mg/day in
the first 6 weeks.
Outcomes Primary: change in chorea (UHDRS-motor, chorea item).
Secondary:
• Change in cognition (UHDRS cognitive, cognitive portion of the Alzheimer Disease Assessment Scale,
WAIS III symbol searching raw score).
• Change in functional status (UHDRS functional assessment).
• Change in quality of life (Sickness Impact Profile scale).
Notes Negative for primary outcome measure.
De Roover J
Methods 9-week double-blind, cross-over study. Washout periods: 1 week pre-trial, no period between blocks.
Method of randomisation: not described.
Results presented as combined data from treatment and placebo periods.
Per-protocol data analysis.
Location: 1 centre (Belgium).
Participants 29 patients, 6 drop-outs. 11 male and 12 female patients (per-protocol cohort).
Mean age of participants: 44.8 years (per-protocol cohort).
Mean disease duration: 2.3 years (per-protocol cohort).
Inclusion criteria: HD (clinical diagnosis and positive family history), stage II/III of Shoulson and Fahn
functional scale, < 60 years.
Exclusion criteria:other neurological or psychiatric disease, alcoholism, poor physical condition. Any
condition liable to cause sedation or interfere with symptom evaluation. Allowed medication: anxiolytics
and antidepressives, except for inhibitors of monoamino oxidase.
Interventions Oral Tiapride 3 g/day, no titration.
Outcomes Change in chorea grade (4-point severity scale).
Change in motor skills (5-point severity scale).
Wakefulness and motor performance (Leeds Psychomotor Tester).
Anxiety, irritability and unsociability (subjective patient assessment).
18Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
De Roover J (Continued)
Depression (Zung self-rating scale).
Blood pressure and side-effects.
Notes Chorea grade (head, p=0.00; trunk , p=0.05; upper limbs, p=0.01; lower limbs, p=0.01) and 3 out of 7
motor skills markedly improved (putting on and taking off socks, p=0-00; drinking from glass, p=0.00;
pouring water from a bottle into a glass, p=0.01).
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Goetz CG
Methods 4-week double-blind, cross-over study. Washout periods: 2 weeks in-between blocks. Method of randomi-
sation: not described.
Results presented as combined data from treatment and placebo periods.
Intention to treat data analysis.
Location: 1 centre (USA).
Participants 10 patients, no drop-outs. 4 male and 6 female patients.
Mean age of participants: 51.6±16.7 years.
Mean disease duration: 6.3±3.6 years.
Inclusion criteria: chorea, dementia and positive family history.
Exclusion criteria: concomitant medication in unconstant dosage.
Interventions Oral L-acetyl-carnitine 45 mg/kg/day, no titration.
Outcomes Disability (Shoulson-Fahn Disability scale).
Abnormal movements (AIMS, reaction time).
Dementia (MMSE, Controlled Oral World Association test).
Depression (Hamilton depression scale).
Global severity assessment (AIMS).
Notes Negative for efficacy measures.
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
19Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Hersch G
Methods 16-week double-blind, parallel study (follow-up: 24 weeks). Method of randomisation: computer gener-
ated blocking and stratification by site.
Results presented for each arm of the study.
Intention-to-treat data analysis.
Location: 10 centres (USA).
Participants 64 patients, 5 drop-outs. 38 male and 26 female patients.
Mean age of participants: 46.3 years.
Mean disease duration: 7.0 ± 4.5 years.
Inclusion criteria: adult, genetically established HD, TFC-UHDRS≥5, caregiver to witness consent and
monitor compliance.
Exclusion criteria: creatine exposure in<30 days; hematological, renal or hepatic disease, leu<3800/mm3;
creatinine>2 mg/dL, ALT >2xnormal, unstable psychiatric or medical conditions.
Interventions Oral creatine 8 mg/day (32 patients) and placebo (32 patients). No titration.
Outcomes Primary: tolerability (rate of treatment failures: non completion of study, drug suspension>1, more than
1 week of drug suspension).
Secondary:
• UHDRS motor, cognitive, behavioral and functional scales.
• 8OH2’dG concentration (plasma).
Notes Safe but no effect on UHDRS scales.
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
INTRO-HD
Methods
Participants
Interventions
Outcomes Primary: tolerability (proportion of patients that completed the first 12 weeks of the trial).
Secondary:
• Tolerability (number and severity of adverse events, number of withdrawals) and safety (changes
in vital signs and laboratory tests).
• Efficacy [change in UHDRS-total; UHDRS-subitems; neuropsychological test - trail making A
and B, Hopkins Verbal Learning test, Digit Span, Digit Ordering task, Conditional Associative
Learning task, Mental Rotation Test, Brief test of Attention, Personality (Frontal lobe Personality
Scale), mood (Beck Depression Inventory)].
20Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
INTRO-HD (Continued)
• Free-radical assays (CSF and plasma).
• OPC-14117 concentration (CSF and plasma).
Notes Negative for efficacy measures.
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Kieburtz K
Methods 6-week double-blind, three-arm parallel study. Method of randomisation: not described.
Results presented for each arm of the study.
Intention-to-treat data analysis.
Location: 1 centre (USA).
Participants 31 patients, 2 drop-outs. 18 male and 13 female patients.
Median age of participants: 48.0 ± 12.2 years.
Median disease duration: 9.6 ± 4.2 years.
Inclusion criteria: genetically established HD.
Exclusion criteria: another neurological illness or injury, poorly controlled epilepsy, end-stage HD (de-
mentia, spasticity, need of continuous care), insulin-dependent diabetes mellitus, major psychiatric disor-
der without stable antidepressant or antipsychotic medication for ≥ 6 months, high dose of antioxidants
(vitamin E).
Interventions Oral remacemide 200 mg/day (10 patients) or 600 mg /day (10 patients) or placebo (11 patients). No
titration.
Outcomes 1. Safety/tolerability (proportion of patients that completed the trial resulting from noncompliance and
development of moderate or severe adverse events)
2. Number and severity of adverse events, occurrence of laboratory abnormalities.
3. Change in functional capacity (HDFCS).
4. Change in chorea grade (HDMRS).
5. Neuropsychological performance (MMSE, Trail making A and B, Symbol Digit test, Stroop Interference
test, three immediate-recall trials of Hopkins Verbal Learning Test, Beck Depression Inventory).
Notes Safe but negative for efficacy measures
Risk of bias
Item Authors’ judgement Description
21Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Kieburtz K (Continued)
Allocation concealment? Unclear B - Unclear
Mateo D
Methods Double 30 minute-infusion with a follow-up of 4 hours in a double-blind, cross-over study. Washout
periods: 2 weeks between trials. Method of randomisation: not described.
Results presented as combined data from treatment and placebo periods.
Intention-to-treat data analysis.
Location: 1 centre (Spain).
Participants 11 patients, no drop-outs. 6 male and 5 female patients.
Mean age of participants: 47.2±10.5 years.
Mean disease duration: 8.9±5.1 years.
Inclusion criteria: not described.
Exclusion criteria: not described.
Interventions Endovenous piracetam 12 g per administration.
Outcomes Involuntary movements (Kartzinel, Hunt, Calne scale).
Notes Worsening of involuntary movements at 4 hours post-infusion (p<0.05).
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
MINO
Methods 8-week (follow-up:1 week) double-blind, parallel study. Method of randomisation: computer generated
blocking and stratification by site.
Results presented for each arm of the study.
Intention-to-treat data analysis.
Location: 8 centres (USA and Canada).
Participants 60 patients, 6 drop-outs. 31 male and 29 female patients.
Mean age of participants: 46.0±9.1 years.
Mean disease duration: 6.7±4.2 years.
Inclusion criteria: confirmed HD (not otherwise specified), >18 years, TFC-UHDRS>5, caregiver to
informed consent and to oversee study medication.
Exclusion criteria: history of minocycline intolerability, WBC<3800/mm3, creatinine >2,0 mg/dL,
ALT>2xULN, unstable medical or psychiatric illness, history of systemic lupus erythematous, anti-nuclear
antibodies>1:40.
22Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
MINO (Continued)
Interventions Oral minocycline 100 or 200 mg/day (18 and 19 patients in each arm, respectively); placebo (matching
placebo; 23 patients). No titration.
Outcomes Primary: tolerability (failure to complete 8 weeks on assigned treatment or more than 1 allowable drug
suspension).
Secondary: UHDRS (motor, cognitive, behavioral, functional).
Notes Safe and tolerated. Treatment assignment did not affected study completion.
Treatment group performed worse in the Stroop interference test: 1.87 ± 4.83 placebo group vs. 1.50 ±
6.68; Minocycline 100 mg/day vs. -3.42 ± 10.5; Minocycline 200 mg/day; p = 0.04.
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Miraxion-Europe
Methods 32-week double-blind, placebo controlled, parallel study.
Method of randomisation: computer generated blocking.
Results presented for each arm of the study.
Modified intention-to-treat data analysis (randomised and at least one post-baseline efficacy assessment).
Location: 27 centres (Europe).
Participants 290 patients.
Inclusion Criteria: >35 years, clinical HD and confirmatory family history of HD, and/or genetic diag-
nosis.
Ambulatory, not requiring skilled nursing care (TFC-UHDRS>7), chorea score(UHDRS)>2 in one ex-
tremity. Maximal dystonia ≤2 and maximal bradykinesia ≤2. Stable dosages of non competitive NMDA
receptor antagonists, and/or antiepileptic medications for 60 days prior to baseline. Females of child-
bearing potential must use adequate birth control.
Exclusion Criteria: history of established diagnosis of tardive dyskinesia, clinical evidence of unstable
medical or psychiatric illness, clinically significant active and unstable psychotic disease (hallucinations
or delusions). Major depression (Beck Depression Inventory [BDI]-II Score >20) at Screening Visit.
Suicidal ideation (BDI-II item 9 ≥ 2) at Screening Visit. History of clinically significant substance
abuse within 12 months of Baseline Visit. Pregnant/lactating women. Participation in other drug studies
within 60 days prior to Baseline Visit. Previous participation in any investigational study of ethyl-EPA
(Miraxion™). Use of aspirin at daily dosage greater than 325 mg/day. Exclusionary Drugs (within 6
months of Baseline Visit): depot neuroleptics. Exclusionary Drugs (within 60 days of Baseline Visit):
omega-3 supplementation, tetrabenazine or reserpine, high dose and/or variable dose oral anti-psychotic
medications, steroid (other than topical), selenium supplements > 55 mcg/day, lithium, benzodiazepines
(except for low dose), anticoagulants.
23Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Miraxion-Europe (Continued)
Interventions Oral ethyl-EPA 2 g/day (147 patients) and placebo (143 patients). No titration.
Outcomes Primary: effect on TMS-4 (UHDRS) at 6 months.
Secondary:
• Chorea (UHDRS).
• TMS (UHDRS).
• Clinical Global Impression (CGI-UHDRS).
Notes Negative for efficacy measures.
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Murman DL
Methods 1-week double-blind, cross-over study. Washout period: 1 week in-between testing days. Method of
randomisation: not described.
Results presented as combined data for each dosage in the treatment and placebo periods.
Data analysis: unclear.
Location: 1 centre (USA).
Participants 10 patients, 0 drop-outs. 4 male and 6 female patients.
Mean age of participants:48.4±12.8 years.
Mean disease duration: 4.7±3.9 years.
Inclusion criteria: autosomal-dominant, neurodegenerative disease and adequate clinical characteristics;
no alternative explanation for the neurologic signs.
Exclusion criteria: CNS medication (antidepressant, antipsychotic), pregnancy, conditions that increase
the exposure risk to ketamine or alter pharmacokinetics, Buschke Selective Reminding Test >5/10 in at
least 1 of 6 trials.
Interventions Endovenous ketamine: escalating dosage of 0.1, 0.4 and 0.6 mg/kg/hr.
Outcomes Primary: cognitive function (verbal - Buschke Selective Reminding Test; visual memory - Washing-
ton Square Picture Memory test; verbal fluency; attention - digit span forward; simple reaction time;
psychomotor skills - finger tapping).
Secondary:
• Motor signs (UHDRS - items 7 to 17).
• Psychiatric and physical symptoms (Institute of Mental Health Self Rating Scale and Brief
Psychiatric Rating Scale).
• Ketamine blood levels.
24Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Murman DL (Continued)
Notes Negative for efficacy measures. Declines in verbal and fluency memory (immediate recall in Buschke
Selective Reminding Test), immediate and delayed recall (Washington Square Picture Memory test) and
in Verbal Fluency test.
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
O’Suilleabhain P
Methods 4-week double-blind, cross-over study. No washout periods. Method of randomisation: not described.
Results presented as combined data from treatment and placebo periods.
Per-protocol data analysis.
Location: 1 centre (USA).
Participants 25 patients, 1 drop-out. 10 male and 14 female patients.
Mean age of participants: 51±13 years.
Mean disease duration: 6 years.
Inclusion criteria: clinical definite or a genetic diagnosis of HD, >18 years, chorea at screening, MMSE>20.
Exclusion criteria: severe psychosis and depression (symptoms of paranoia, hallucinations, suicidal).
Interventions Oral amantadine 300 mg/day. No titration.
Outcomes Primary: change in maximal chorea grade (24-point scale).
Secondary:
• Change in chorea grade questionnaire (patient view).
• Number of errors in a proprioception task.
Notes Negative for primary outcome measure.
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
25Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Quinn N
Methods 9-week double-blind, cross-over study. Washout periods: 2 weeks pre-trial; 1 week in-between blocks.
Method of randomisation: not described.
Results presented individually for each patient.
Per-protocol data analysis.
Location: 1 centre (UK).
Participants 11 patients, 1 drop-out , 7 male and 4 female patients.
Mean age of participants: 53.0 years.
Mean disease duration: 6.7 years.
Inclusion criteria: HD (not otherwise specified).
Exclusion criteria: use of neuroleptics in preceding 2 weeks.
Interventions Oral Sulpiride 300-1200 mg/day. Titration 300 mg in each week (mean dosage: 1054 mg/day).
Outcomes Reduction in dyskinesia (movement count, a combined score for abnormal movements).
Functional capacity.
Notes Improvement in median movement count (38 -placebo- vs 14 -sulpiride - ; p<0.01) and chorea severity
score (33 -placebo- vs 29 -sulpiride-; p<0.01).
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
RID-HD
Methods 8-week double-blind, three-arm parallel study. Method of randomisation: computer generated blocking
and stratification.
Results presented for each arm of the study.
Intention-to-treat data analysis.
Location: 9 centres (USA and Canada).
Participants 63 patients, 7 drop-outs. 31 male and 32 female patients.
Mean age of participants: 47.4±9.1 years.
Mean disease duration: 5.5±3.5 years.
Inclusion criteria:confirmed HD by family history and CAG≥37 repeats, TFC-UHDRS≥7, caregiver to
witness consent and medication compliance.
Exclusion criteria: intolerability to riluzole, exposure to riluzole within 3 months of baseline, pregnancy,
breast-feeding, inadequate contraception, WBC<3800/mm3, creatinine>2 mg/dL, ALT>2xULN, unsta-
ble medical or psychiatric condition, and any of the following medication within 4 weeks of baseline:
investigational drug, glutamatergic drugs, cytochrome P450 1A2 inhibitors, anticonvulsants, potentially
hepatotoxic medications. Antidepressants or neuroleptics in unstable dosage for 4 weeks.
26Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
RID-HD (Continued)
Interventions Oral riluzole 100 or 200 mg/day (18 and 23 patients in each arm, respectively) ; placebo (matching
placebo; 22 patients). No titration.
Outcomes Primary: change in maximal chorea (UHDRS).
Secondary:
• TMS (UHDRS).
• Total dystonia score (UHDRS).
• Stroop Interference Test (UHDRS).
• Independence Scale (UHDRS).
• Safety and tolerability (proportion of patients not completing the study, occurrence and severity
of adverse events, number of treatment suspensions or withdrawals, changes in blood pressure
and laboratory test abnormalities.
Notes Reduction in chorea at 8 weeks for an efficacious dosage of 200 mg/d: -0.2 ±2.9 points (100 mg), -2.2±3.3
points (200 mg) and 0.7±3.4 points (placebo). Excess of hepatoxicity with efficacious dosage.
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
Roos RA
Methods 4-week double-blind, cross-over study. No washout period. Method of randomisation: not described.
Results presented as combined data from treatment and placebo periods.
Intention-to-treat data analysis.
Location: 1 centre (Belgium).
Participants 22 patients with no drop-outs. 9 male and 13 female patients.
Mean age of participants: 49 years.
Mean disease duration: not described.
Inclusion criteria: clinical and genetically proven HD, <70 years of age, normal liver and kidney function.
Exclusion criteria: systemic diseases and other disorders of central nervous system.
Interventions Oral Tiapride 300 mg/day, no titration.
Outcomes Total number of choreic movements during 2 minutes (video and doppler-radar recording).
Self-assessment analogue 3-point scale for patient and a 5-point scale for family.
Side-effects (quantification of a parkinsonian effect - motor performance speed) and questionnaire for
patient about AE.
Notes Negative for efficacy measures. No carry-over effect documented.
27Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Roos RA (Continued)
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Stocchi F
Methods 4-week open trial followed by 4-week double-blind, parallel study. Method of randomisation: not de-
scribed.
Results presented for each arm of the study.
Intention-to-treat data analysis.
Location: 1 centre (Italy).
Participants 10 patients with 0 drop-outs. 5 male and 5 female patients.
Mean age of participants: 52.2±13.9 years.
Mean disease duration: 3.8±1.1 years.
Inclusion criteria: clinical signs and positive family history of HD.
Exclusion criteria: not described.
Interventions Oral Transdihydrolisuride 5 mg/day and placebo. No titration.
Outcomes Disease severity (Marsden-Quinn Rating Scale).
AIMS.
MMSE.
Rapid wrist movements (neurophysiological recording).
Notes Results given to the full extension of the trial.
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
28Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TETRA-HD
Methods 13-week double-blind (follow-up:1 week), unbalanced (treatment:placebo - 2:1) parallel study. Method
of randomisation: computer generated.
Results presented for each arm of the study.
Intention-to-treat data analysis.
Location: 16 centres (USA).
Participants 84 patients, 6 drop-outs. 32 male and 52 female patients.
Mean age of participants: 49.2±9.1 years.
Mean disease duration: 8.3±4.6 years.
Inclusion criteria: chorea, family history, CAG≥37. Ambulatory independent, TFC-UHDRS>5, chorea-
UHDRS≥5. Presence of caregiver.
Exclusion criteria: disabling depression, dysphagia or dysarthria, treatment with TBZ or with dopamine-
depleting drug, monoamine oxidase inhibitors, levodopa, dopamine agonist, amantadine or memantine.
Off dopamine D2 blockers for <4 weeks, unstable dosage of benzodiazepines or antidepressant in previous
8 weeks.
Interventions Oral tetrabenazine 100 mg/day (maximum dose for titration) (30 patients) and placebo (identical in
appearance, 54 patients). (mean dosage=not available).
Outcomes Primary: change in total maximal chorea (UHDRS).
Secondary:
• Change in CGI (UHDRS).
• Change in total motor score (UHDRS).
• Gait score (UHDRS).
• Functional checklist (UHDRS).
Notes Change in chorea grade (-5.0±0.5 tetrabenazine vs -1.5±0.7 placebo; p=0.0001).
Change in CGI (3.0±0.2 tetrabenazine vs 3.7±0.2 placebo; p=0.007).
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
TREND-HD
Methods 32-week double-blind, placebo controlled, parallel study. Method of randomisation: computer generated
blocking.
Results presented presented for each arm of the study.
Modified intention-to-treat data analysis (randomised and at least one post-baseline efficacy assessment).
Location: 41 centres (USA and Canada).
29Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TREND-HD (Continued)
Participants 316 patients.
Inclusion Criteria: >35 years, clinical HD and confirmatory family history of HD, and/or genetic diagnosis.
Ambulatory, not requiring skilled nursing care (TFC-UHDRS>7), chorea score (UHDRS)>2 in one
extremity. Maximal dystonia ≤2 and maximal bradykinesia ≤2 Stable dosages of non-competitive NMDA
receptor antagonists, and/or antiepileptic medications for 60 days prior to baseline. Females of child-
bearing potential must use adequate birth control.
Exclusion Criteria: History of established diagnosis of tardive dyskinesia, clinical evidence of unstable
medical or psychiatric illness, clinically significant active and unstable psychotic disease (hallucinations or
delusions). Major depression (Beck Depression Inventory [BDI]-II Score>20) at Screening Visit. Suicidal
ideation (BDI-II item 9≥2) at Screening Visit. History of clinically significant substance abuse within 12
months of Baseline Visit. Pregnant/lactating women. Participation in other drug studies within 60 days
prior to Baseline Visit. Previous participation in any investigational study of ethyl-EPA (Miraxion™)
.Use of aspirin at daily dosage greater than 325 mg/day. Exclusionary Drugs (within 6 months Baseline
Visit): Depot neuroleptics. Exclusionary Drugs (within 60 days Baseline Visit): Omega-3 supplementa-
tion, tetrabenazine or reserpine, high dose and/or variable dose oral anti-psychotic medications, steroid
(other than topical), selenium supplements>55 mcg/day, lithium, benzodiazepines (except for low dose),
anticoagulants.
Interventions Oral ethyl-EPA 2 g/day (158 patients) and placebo (158 patients). No titration .
Outcomes Primary: effect on TMS-4 (UHDRS) at 6 months.
Secondary:
• Chorea (UHDRS).
• TMS (UHDRS).
• Clinical Global Impression (CGI-UHDRS).
Notes Results given to the all extension of the trial. The results from a 6-month open label extension phase are
expected.
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
Vaddadi K
Methods 2-year double-blind, parallel study. Method of randomisation: not described.
Results presented for each arm of the study.
Per-protocol data analysis.
Location: 1 centre (Australia).
30Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Vaddadi K (Continued)
Participants 19 patients, 2 drop-outs. 8 male and 9 female patients (per-protocol cohort).
Mean age of participants: 49.8 ± 8.5 years (per-protocol cohort).
Inclusion criteria: genetically established HD.
Exclusion criteria: any other neurological illness or injury, poorly controlled epilepsy, end-stage HD
(dementia, spasticity, continuous care needed), insulin-dependent diabetic, major psychiatric disorder
without stable antidepressant or antipsychotic medication for ≤ 6 months, high dose of antioxidants (vit.
E).
Interventions Oral unsaturated fatty acids (acids linoleic, gamma-linolenic, dihomo-gammalinolenic, ethyl-eicosapen-
taenoic acid, docosahexaenoic acid, alpha-lipoic acid) 8 g/day (9 patients) and placebo (identical appearing
capsule containing hydrogenated coconut oil and anti-oxidants as in active treatment) in 8 patients.
Outcomes Change in dyskinesia (Rockland-Simpson Dyskinesia Rating Scale).
Change in UHDRS items: motor, functional, behavioural and cognitive.
Notes Anti-dyskinetic effect: 7.0±3.7 (placebo) vs -4.3±2.1 (active), p=0.01. Results from an average follow-up
of 19 and 20 months for treatment and placebo, respectively.
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
van Vugt J
Methods 4-week double-blind, parallel study. Method of randomisation: not described.
Results presented for each arm of the study, after grouping for neuroleptic previous use.
Per-protocol data analysis.
Location: 1 centre (The Netherlands).
Participants 33 patients, 7 drop-outs. 15 male and 18 female patients.
Mean age of participants: 48.4±10.8 years.
Mean disease duration: 9.4±5.9 years.
Inclusion criteria: clinically and genetically established HD with typical choreatic movements.
Exclusion criteria: demented/psychotic or history of clozapine use.
Interventions Oral clozapine 150 mg/day (maximum dosage). Titration: 25 mg each day during the first week. (mean
dosage=not available).
Outcomes 1. Change in chorea grade (AIMS, UHDRS chorea).
2. Voluntary motor performance (UHDRS motor).
3. Functional capacity (modified PD self-reported disability scale).
4. Semi-quantitative patient questionnaire.
31Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
van Vugt J (Continued)
5. Partner evaluated disability questionnaire.
Notes Negative for efficacy measures.
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
Verhagen Metman L
Methods 4-week double-blind, cross-over study. No washout period. Method of randomisation: random number
tables with blocking,
Results presented as combined data from treatment and placebo periods.
Per-protocol data analysis.
Location: 1 centre (USA)
Note: the authors explain the non-inclusion of a washout period by the relative short half-life of amantadine
(12 hours in young adults) and the extrapolation of the clinical observation that a carry-over of the
antidyskinetic effect of amantadine in Parkinson’s disease is limited to 2 to 3 days.
Participants 24 patients, 2 drop-outs. 16 male and 8 female patients.
Median age of participants: 52 years (range: 32-68 years).
Median disease duration: 6 years (range: 2-15 years).
Inclusion criteria: HD confirmed by genetic testing or family history, ratable chorea, ambulatory, ability
of complying and reporting compliance and adverse events.
Exclusion criteria: renal impairment (elevated plasma creatinine), MMSE<18/30, past history of psychosis,
concomitant conventional neuroleptic use (not on a steady low-dose).
Interventions Oral amantadine 100-400 mg/day; titration within 4 days (mean dosage: 386 mg/d).
Outcomes Primary: chorea severity (UHDRS-28-point scale) at rest and at its maximum - by videotape.
Secondary:
• Change in maximal and at rest chorea (UHDRS) - live.
• Parkinson score (motor UHDRS; items 6,7,9, 10) - live.
• Plasma amantadine levels.
• Cognitive test battery (MMSE, Repeated Battery for the Assessment of Neurological Syndromes,
Verbal Fluency Test, Symbol Digit Modalities Test, Stroop Interference Test).
• Safety and tolerability.
Notes Reduction for maximal median chorea (18% vs 5%, p=0.0007).
Reduction for rest median chorea (25% vs 5%, p=0.013).
32Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Verhagen Metman L (Continued)
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
AE - Adverse events.
AIMS - Abnormal Involuntary Movement Scale.
ALT - Alanine aminotransferase.
ANA - Anti-nuclear antibody.
CAG - Glutamine.
CGI - Clinical Global Impression.
CNS - Central Nervous system.
EKG - Electrocardiogram.
EPA - Eicosapentaenoic acid.
HD - Huntington’s disease.
HDFCS - Huntington Disease Functional Capacity.
HDMRS - Huntington Disease Rating Motor Scale.
Hx - History.
L-DOPA - Levo-3,4-dihydroxy-L-phenylalanine.
MMSE - Mini-Mental State Examination.
NMDA - M-methyl-D-asparte.
OPC - Oligomeric Proanthocyanidins.
SLC-90R - Symptom Checklist-90-R.
TBZ - Tetrabenazine.
TFC - Total Functioning Capacity.
TMS - Total Motor Score.
UHDRS - Unified Huntington Disease Revised Scale.
ULN - Upper-limit normal.
vs- versus.
WBC - White blood count.
80H2’dG - 8-Hydroxy-2’-deoxyguanosine.
Characteristics of excluded studies [ordered by study ID]
Albanese A n<10
Albano C open-label study
Alpay M case series
Aminoff MJ n<10
33Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
Asher SW n<10
Barr AN open-label study
Bassi S (a) open-label study
Bonelli RM open-label study
Bonuccelli U open-label study
Braun A n<10
Caine ED n<10
Caparros-Lefebvre D case series
Caraceni TA (a) open-label study
Caraceni TA (b) n<10
Caraceni TA (c) open-label study
Carman JS n<10
Corsini GU n<10
Dalby M open-label study
Dallochio C open-label study
de Tommaso (a) open-label study
de Tommaso (b) open-label study
de Tommaso (c) open-label study
Destée A n<10
Dupont E n<10
Fernandez HH open-label study
Fisher R (a) not randomised
34Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
Fisher R (b) not randomised
Fog R open-label study
Foster NL n<10
Frattola L (a) Jadad score<3
Frattola L (b) open-label study
Giménez-Roldán S not controlled
Girke W n<10
Girotti F open-label study
Giuffra ME n<10
Gray MW open-label study
Haslam MT open-label study
Heckman JM n<10
Jankovic J n<10
Kartzinel R n<10
Leng TR no blinding
Leonard DP n<10
Lucetti C(a) open label study
Lucetti C(b) n<10
Manyam BV n<10
Mattson B open-label study
McLellan D n<10
Nutt JG (a) n<10
Nutt JG (b) n<10
35Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
Ondo WG not controlled
Pakkenberg H open-label study
Paleacu D open-label study
Pearce I open-label study
Perry TL (a) open-label study
Perry TL (b) n<10
Perry TL (c) n<10
Piccinin G n<10
Saft C (a) case series
Saft C (b) open-label study
Scigliano G n<10
Scotti G open-label study
Seppi K open-label study
Shoulson I(a) n<10
Shoulson I(b) not randomised
Shults C n<10
Squittieri F open-label study
Swash M not controlled
Symington GR n<10
Tarsy D n<10
Tell G not controlled
Terrence CF n<10
Tolosa ES open-label study
36Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
Tourian AY outcome meaures not clinical
Van Duijn E case series
Vestergaard P n<10
Vitale P n<10
Walker FO open-label study
Worrall EP n<10
Zesiewicz T open-label study
Zinzi P not controlled
Swash M - two studies published in the same article: 1) non-controlled with tetrabenazine and 2) tetrabenazine vs amantadine. Only
two Huntington´ s disease patients were included.
Characteristics of studies awaiting classification [ordered by study ID]
Curtis A
Methods Randomised, double-blind, placebo-controlled, cross-over study. Washout periods: 5 weeks in-between blocks.
Participants 44 patients with HD.
Interventions Oral nabilone, 1-2 mg/day during 15-week.
Outcomes Primary: change in TMS-UHDRS.
Secondary: change in behaviour and cognitive scales (UHDRS), change in SF-36 scale, neuropsychiatric Inventory.
Notes Data as in http://clinicaltrials.gov.
DIMOND-A
Methods Non-randomised, open label, uncontrolled, single group assignment, safety study.
Participants Clinical features of HD and confirmatory family history of HD or a CAG repeat expansion≥ 36, Stage I,II,III HD
and a TFC-UHDRS≥5.
Interventions Dimebon 30 or 60 mg/day for 7 days.
37Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DIMOND-A (Continued)
Outcomes Primary: Dose-limiting toxicity.
Secondary: UHDRS.
Notes Data as in http://clinicaltrials.gov.
PHEND-HD
Methods Randomised, double-blind, placebo-controlled, in parallel safety study.
Participants Subjects with clinical diagnosis of HD and family history of HD or a CAG repeat expansion≥37, TFC-UHDRS≥7,
Stages I, II HD and TFC ≥7.
Interventions Sodium phenylbutyrate 15g/day vs. placebo.
Outcomes Primary: proportion of subjects able to complete treatment.
Secondary: various parameters of safety, tolerability, motor, cognitive and functional (UHDRS), biochemical and
genetic measures.
Notes Data as in http://clinicaltrials.gov.
38Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Characteristics of ongoing studies [ordered by study ID]
Atomoxetine
Trial name or title Atomoxetine for Attention Deficits in Adults With Mild HD: A Randomised, Placebo-Controlled Crossover
Study
Methods Randomised, double-blind (Subject, Caregiver, Investigator, Outcomes Assessor), cross-over design,
safety/efficacy study.
Participants Confirmed Huntington’s disease diagnosis, mild HD, complaints of poor attention.
Interventions Atomoxetine 40 mg/day vs. placebo.
Outcomes Primary: CAARS score and cognitive summary score
Secondary: individual cognitive tests, UHDRS motor score, SCL-90-R global index score.
Starting date November 2005.
Contact information Leigh Beglinger, Ph.D., University of Iowa.
Notes Data as in http://clinicaltrials.gov.
CIT-HD
Trial name or title A randomised, placebo-controlled pilot study in Huntington’s Disease (CIT-HD).
Methods Randomised, double-blind, placebo-controlled, parallel design, efficacy study.
Participants Diagnosis of HD (confirmatory genetic testing, presence of unequivocal motor signs of HD (e.g., chorea) in
combination with a positive family history.
Interventions Citalopram 20mg/day vs. placebo during 16 weeks.
Outcomes Primary: effect on executive function.
Secondary: relation between executive function and functional status, effect on functional measures (health-
related quality of life, work productivity, and self-reported attention), motor performance, and psychiatric
status, effect on volumetrics and metabolics (i.e., N-Acetyl-Aspartate concentration) of neostriatum.
Starting date November 2005.
Contact information William H Adams: phone: 1-319-353-4411)/ e-mail: [email protected].
Nicole R Ramza: phone:319-384-9408 / e-mail: [email protected].
Notes Data as in http://clinicaltrials.gov.
39Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Memantine
Trial name or title A pilot study of Memantine for cognitive and behavioral dysfunction in Huntington’s disease.
Methods Randomised, double-blind (Subject, Caregiver, Investigator, Outcomes Assessor), cross-over design,
safety/efficacy study.
Participants Diagnosis of HD with current complaints of memory or concentration difficulties.
Interventions First 3 months, memantine 20 mg/day vs. placebo. Last 3 months, open label.
Outcomes Primary: sensitive neuropsychological battery.
Secondary: behavioral and functional measures at 3 and 6months of treatment.
Starting date
Contact information Jody Corey-Bloom, MD, PhD: phone: 858-642-3470 / e-mail: [email protected].
Notes Data as in http://clinicaltrials.gov.
ADHD - Attention Deficit/Hyperactivity Disorder.
CAG - Glutamine.
CAARS - Conner’s Adult ADHD Rating Scales.
HD -Huntington’s disease.
SCL-90-R - Symptom Checklist-90-R.
TFC - Total Functioning Capacity.
UHDRS -Unified Huntington Disease Revised Scale.
40Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
D A T A A N D A N A L Y S E S
Comparison 1. Amantadine
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Change in maximal chorea (%) 2 93 Std. Mean Difference (IV, Random, 95% CI) -0.25 [-0.93, 0.43]
Analysis 1.1. Comparison 1 Amantadine, Outcome 1 Change in maximal chorea (%).
Review: Therapeutic interventions for symptomatic treatment in Huntington’s disease
Comparison: 1 Amantadine
Outcome: 1 Change in maximal chorea (%)
Study or subgroup Treatment Control Std. Mean Difference Weight Std. Mean Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI
Verhagen Metman L 22 -11.43 (16.54) 22 -1.79 (14.8) 48.6 % -0.60 [ -1.21, 0.00 ]
O’Suilleabhain P 24 0 (14.33) 25 -1.25 (13.13) 51.4 % 0.09 [ -0.47, 0.65 ]
Total (95% CI) 46 47 100.0 % -0.25 [ -0.93, 0.43 ]
Heterogeneity: Tau2 = 0.15; Chi2 = 2.71, df = 1 (P = 0.10); I2 =63%
Test for overall effect: Z = 0.71 (P = 0.48)
-2 -1 0 1 2
Favours treatment Favours control
W H A T ’ S N E W
Last assessed as up-to-date: 22 December 2007.
11 August 2008 Amended Converted to new review format.
41Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
H I S T O R Y
Protocol first published: Issue 2, 2007
Review first published: Issue 3, 2009
23 December 2007 New citation required and conclusions have changed Substantive amendment
C O N T R I B U T I O N S O F A U T H O R S
Protocol - Ferreira J, Mestre T, Sampaio C.
Literature search - Ferreira J, Mestre T, Coelho M.
Literature selection - Ferreira J, Mestre T, Coelho M.
Papers quality assessment - Ferreira J, Mestre T.
Data collection from papers - Ferreira J, Mestre T.
Interpretation of data - Ferreira J, Mestre T, Coelho M, Rosa MM, Sampaio C.
Review writing - Mestre T, Ferreira J, Sampaio C.
D E C L A R A T I O N S O F I N T E R E S T
Mestre T, Ferreira J, Coelho M, Rosa MM were investigators in a clinical trial to investigate the efficacy of ethyl-EPA for the treatment
of HD.
S O U R C E S O F S U P P O R TInternal sources
• Movement Disorders Cochrane Review Group, Portugal.
• Neurological Clinical Research Unit, Institute of Molecular Medicine, Portugal.
External sources
• No sources of support supplied
42Therapeutic interventions for symptomatic treatment in Huntington’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.