Drugs 2010; 70 (5): 561-571

REVIEW ARTICLE 0012-6667/10/0005-0561/$55.55/0

ª 2010 Adis Data Information BV. All rights reserved.

Advances in the Pharmacological

Management of Huntington’s Disease
Samuel Frank1 and Joseph Jankovic2
1 Boston University School of Medicine, Boston, Massachusetts, USA
2 Baylor College of Medicine, Houston, Texas, USA

Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561
1. Pathogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562
2. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562
3. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563
4. Pharmacological Treatment Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564
4.1 Tetrabenazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565
4.2 Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565
4.3 Other Antichorea Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566
5. Potential Neuroprotective and Experimental Strategies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568

Abstract There is inevitable physical, cognitive and behavioural decline in Hun-

tington’s disease (HD), a dominantly inherited progressive neurological
disorder. The hallmark of the disease is chorea, an involuntary brief move-
ment that tends to flow between body regions. HD is diagnosed clinically with
genetic confirmation. Predictive testing is available; however, it should be
undertaken with caution in patients at risk for the disease but without clinical
disease expression. Ongoing observational trials have identified not only
early subtle motor signs, but also striatal volume, verbal memory and olfac-
tion as possible early manifestations of clinical disease. Multiple areas of
the brain degenerate, with dopamine, glutamate and GABA being the pre-
dominant neurotransmitters affected in HD. Although many pharmaco-
therapies have been evaluated targeting these neurotransmitters, few well
conducted trials for symptomatic or neuroprotective interventions have
yielded positive results. Tetrabenazine is one of the better studied and more
effective agents for reducing chorea, although with a risk of potentially ser-
ious adverse effects. Newer antipsychotic agents such as olanzapine and
aripiprazole may have adequate efficacy with a more favourable adverse-effect
profile than older antipsychotics for treating chorea and psychosis. In this
review, the pathogenesis, epidemiology and diagnosis of HD are discussed as
background for understanding potential pharmacological treatment options.
Potential strategies to delay the progression of HD that have been studied
and are planned for the future are summarized. Although there is no current
562
method to change the course of this devastating disease, education and
symptomatic therapies are effective tools available to clinicians and the fa-
milies affected by HD.
Huntington’s disease (HD) is a hereditary,
progressive neurodegenerative disease clinically
characterized by abnormal involuntary move-
ments, behavioural disturbance, cognitive dys-
function and psychiatric disease. The disease is
caused by a CAG (glutamine) trinucleotide ex-
pansion in exon 1 of the huntingtin gene (HTT) at
the location 4p16.9.[1] The function of huntingtin
protein (HTT) is not known, but it may be in-
volved in internal cell signalling, maintenance of
cyclic adenosine monophosphate response ele-
ment binding (CREB) protein and preventing
neuronal toxicity.[2] There is early evidence to
suggest that the binding of the protein Rhes (Ras
homologue enriched in striatum) to huntingtin
may be necessary to cause cellular toxicity.[3]
Although there is no established treatment to
delay the onset or forestall the progression of
HD, symptomatic treatment of chorea may be
beneficial in some individuals, as it may have a
favourable effect on motor function, quality of
life and safety.[4-6] Since pathogenesis-targeted
therapy is a desirable goal, we first briefly review
current hypotheses about the pathogenesis of
HD, but the chief focus is on symptomatic and
experimental treatment strategies.
For this review, the search strategy began with a
PubMed search with the term Huntington’s disease
(limits of Huntington’s disease in the title/abstract
field and English, human, clinical trials) that yield-
ed 175 original articles (search last run on 15
December 2009). Additional trials of an older
nature were identified using the same search re-
strictions with the outdated keyword Huntington’s
chorea (65 original articles). Further ongoing trials
were identified using www.clinicaltrials.gov and
the search term Huntington’s disease in the condi-
tion field, yielding 47 results.
1. Pathogenesis
Pathologically, HD is associated with diffuse
loss of neurons, particularly involving the cortex
ª 2010 Adis Data Information BV. All rights reserved.
Frank & Jankovic
and the striatum. Medium spiny neurons in the
striatum that contain GABA and enkephalin are
affected early in the disease, and are the primary
neurons targeted in HD. These neurons typically
project to the lateral globus pallidus. There is
then progression to the remainder of the basal
ganglia with subsequent dissemination, including
the cortex and substantia nigra. There are intra-
nuclear and cytoplasmic inclusions of the ag-
gregate HTT. Huntingtin is cross-linked with
other soluble HTT to form the inclusion bodies in
neurons. It is not known if the accumulation of
HTT conglomerate results in cell death or if the
soluble form of the protein is the toxic form.[7,8]
Although dopamine, glutamate and GABA
are thought to be most affected in HD and
are targeted for treatment, multiple neuro-
transmitters and their receptors are involved in
various regions in the HD brain (table I).[9-22]
There is typically a sequence and pattern of re-
ceptor changes that emerges with degeneration in
HD, beginning with cannabinoid and adenosine
A2a receptor binding in the striatum and globus
pallidus externa (GPe). There is also increased
GABAA receptor binding in the GPe.
As the disease progresses, there is typically loss
of dopamine D1 receptors in the striatum as well as
cannabinoid and D1 receptors in the substantia
nigra, eventually involving the rest of the basal
ganglia.[9] The preferential loss of enkephalinergic
striatal neurons correlates with the appearance
of chorea.[10,11] Loss of substance P/dynorphin
neurons correlates with the increase in dystonia in
the later stages of disease.[12]
2. Epidemiology
Most European populations show a pre-
valence rate of 4–8 per 100 000, and HD may be
as frequently seen in India and parts of central
Asia.[23] More recent studies in other European
nations have confirmed this prevalence rate.[24,25]
HD is notably rare in Finland and Japan, but
Drugs 2010; 70 (5)
Pharmacological Management of Huntington’s Disease 563

Table I. Receptors involved in Huntington’s disease[9-22] nosis. Recent evidence has been published ex-
Receptor Location Stage of disease amining those who are gene positive but not yet
Adenosine A2a Striatum, Gpe Preclinical to advanced symptomatic by motor criteria (TRACK-HD,
Cannabinoid Striatum, GPe Preclinical to advanced Neurobiological Predictors of Huntington’s
Dopamine D1 Striatum, substantia Clinical diagnosis to Disease Trial [PREDICT-HD] and Prospective
nigra advanced Huntington at Risk Observational Study
Dopamine D2 Caudate, putamen Prodromal [PHAROS]).[29-31] There is also a study currently
Dynorphin Striatum Emergence of dystonia prospectively enrolling subjects with HD and their
Enkephalin Striatum Emergence of chorea affected and unaffected family members to further
GABA Striatum Advanced understand biomarkers of disease and signs of
Glutamate Cortical Preclinical to advanced onset (Cooperative Huntington’s Observational
Substance P Striatum Emergence of dystonia Research Trial [COHORT]).[32] The focus of the
GPe = globus pallidus externa. COHORT study is not neuroimaging, but rather
clinical measures and biological samples.
Subtle motor abnormalities have been asso-
data for eastern Asia and Africa are inadequate. ciated with a smaller striatal volume and higher
There are also well known large populations of probability of disease diagnosis.[29] Lower scores
patients with HD in Scotland and the Lake on the Hopkins Verbal Learning Test-Revised
Maracaibo region of Venezuela.[26,27] The dis- were associated with closer proximity to diag-
order may be underestimated in the Black nosis and smaller striatal volumes.[33] Subjects
American population. There have been no wide- with an expanded repeat and preclinical diag-
spread epidemiological studies of HD in the US nosis of HD also had less accurate recognition of
since the wide availability of genetic testing, but it negative emotions.[34] In addition, motor ex-
is estimated that approximately 25 000–30 000 amination score, striatal volume, speeded finger
individuals have manifest HD and a further tapping, self-timed finger tapping, word list
150 000–250 000 individuals are at risk for HD. learning and odour identification in subjects in
Men and women are affected equally and typi- the PREDICT-HD study were all associated with
cally become symptomatic in the third and the predicted time to diagnosis.[35] Expansion-
fourth decades. The symptoms of HD can start at positive individuals also reported more psychiatric
any age ranging from 1 to 90 years. Approxi- symptoms (depression, anxiety, obsessive-compul-
mately 5–10% of cases are classified as juvenile siveness) than expansion-negative individuals.[36]
onset, with symptoms starting before the age of The TRACK-HD study has confirmed some and
20 years. The vast majority of juvenile cases are expanded upon findings in PREDICT-HD in that
inherited paternally, and in place of chorea, pa- presymptomatic subjects had significant changes in
tients may exhibit more parkinsonian signs of whole-brain volume, regional grey and white mat-
bradykinesia, dystonia, tremors and a cognitive ter differences, impairment in a range of motor
deficit.[28] When patients exhibit more hypo- tasks, oculomotor findings, and cognitive and
kinetic features, they are said to have the Westphal neuropsychiatric dysfunction.[30] The various mo-
variant of HD. tor and non-motor measures on the neurological
examination used to diagnose and track HD are
included in the Unified Huntington Disease Rating
3. Diagnosis Scale (UHDRS).[37] The scale is divided into six
sections: motor, cognitive, behavioural and three
HD is diagnosed based on the combination of functional scales (total functional capacity, func-
motor, behavioural and cognitive symptoms in tional checklist and the independence scale).
the setting of a family history of the disease. A Based on the guidelines published by the
DNA test showing abnormal CAG expansion in American College of Genetics, patients with 40 or
the HTT gene can be used to confirm the diag- more repeats have 100% penetrance.[38] In other

ª 2010 Adis Data Information BV. All rights reserved. Drugs 2010; 70 (5)
564
words, if patients have 40 or more copies of the
gene, they will inevitably express the disease
clinically. In patients with a CAG repeat length in
the 36–39 range, there is reduced penetrance with
increased likelihood of expression occurring with
longer length of repeats and with longer lifespan
of the patient. Patients with fewer than 36 repeats
will generally not develop clinical disease, al-
though there are case reports of patients who
manifest HD in this range.[39,40] Patients with an
allele repeat size of 27–35 have demonstrated
meiotic instability, particularly in sperm, indi-
cating that the following generation is at higher
risk of inheriting an expanded number of repeats,
increasing the risk of clinical disease. The length
of repeat size correlates generally with the age of
onset, but not necessarily with the severity or
duration of disease (figure 1).[41]
The course of the disease is typically 15–20
years, with dementia, mutism, dystonia and bra-
dykinesia predominating in end stages. Patients
with more dystonia and swallowing issues may
experience accelerated complications and, there-
fore, shorter lifespan. Chorea may become a
safety issue with larger amplitude movements
causing injury or malpositioning, and frequent
movements resulting in skin injuries, infections or
even fractures and head trauma. Cause of death is
typically related to complications of immobility
such as skin breakdown, pneumonia, cardiac
disease or infection. However, 25% of patients
Age at onset of symptoms (y)
90
40
1
20 44 100
CAGn
Fig. 1. On average, the larger the repeat size of CAG sequence
inherited, the younger the age of onset of Huntington’s disease (HD).
The median number of repeats (CAGn) inherited for HD is 44, with a
mean age at onset of about 40 years.
ª 2010 Adis Data Information BV. All rights reserved.
Frank & Jankovic
attempt suicide, which is a cause of death in 8–9%
of patients.[42]
Behavioural dyscontrol can be a severely dis-
abling symptom of HD, causing distress to the
patient, family and caregivers. Environmental
approaches and cognitive interventions are the
mainstay of treatments, but pharmacological
agents can augment addressing disruptive beha-
viours. Depression, anxiety, aggressive, impulsive
and obsessive-compulsive behaviours are also
frequently treated pharmacologically and require
behavioural intervention, but caution should be
used to avoid oversedation and apathy, already
common in HD patients.
4. Pharmacological Treatment Options
Many agents and surgical procedures have
been evaluated in HD for their antichoreic effi-
cacy, including dopamine-depleting agents, do-
pamine antagonists, benzodiazepines, glutamate
antagonists, acetylcholinesterase inhibitors,
dopamine agonists, antiseizure medications, can-
nabinoids, lithium, deep brain stimulation and
fetal cell transplantation.[43-46] Pharmacological
interventions typically address the hyperkinetic
movement disorders (chorea, dystonia, ballism,
myoclonus and tics), but may also affect psy-
chiatric issues (irritability, depression, anxiety,
mania, apathy, obsessive-compulsive disorder) or
cognitive decline associated with HD. Adjunctive
therapies, alternative and complementary thera-
pies, behavioural plans and cognitive interven-
tions also play a critical role in addressing the
symptoms of HD.
Several excellent guidelines on the sympto-
matic treatment of HD have been published.[43-53]
Overall, there is far too little evidence available to
guide long-term symptomatic treatment in HD,
and double-blind and long-term studies assessing
various treatment strategies in HD are needed.[49]
A Cochrane review examined 22 trials (1254
participants); 9 trials had a crossover design and
13 were conducted in parallel. The studies ex-
amined were of relatively short duration, ranging
from 2 to 80 weeks. Various pharmacological
interventions were studied including anti-
dopaminergic drugs (five studies), glutamate
Drugs 2010; 70 (5)
Pharmacological Management of Huntington’s Disease
receptor antagonists (five studies) and energy
metabolites (five studies). The authors concluded
that based on available evidence, only tetra-
benazine showed clear efficacy for the control of
chorea, but ‘‘no statement can be made regarding
the best medical practice for the control of motor
and non-motor symptoms in HD.’’
4.1 Tetrabenazine
Tetrabenazine is the only US FDA-approved
drug for HD and is indicated for the treatment
of chorea associated with HD. In addition to the
US and Canada, tetrabenazine is marketed in
Australia, Denmark, France, Germany, Ireland,
Israel, Italy, New Zealand, Portugal, Spain,
Switzerland and the UK. By reversibly inhibiting
the central vesicular monoamine transporter type
2 (VMAT2), tetrabenazine depletes dopamine
more selectively than it depletes noradrenaline
(norepinephrine).[54,55] The highest binding dens-
ity for tetrabenazine is in the caudate nucleus,
putamen and nucleus accumbens, areas known to
bear the brunt of pathology in HD.[56,57] VMAT2
binding and monoamine depletion by tetra-
benazine is reversible, lasts hours and is not
modified by long-term treatment.[58,59] These
features of the drug differentiate it from the other
dopamine-depleting agent reserpine that binds
not only to VMAT2 but also to VMAT1, which is
localized to the peripheral nervous system. The
peripheral binding accounts for some of the
peripheral adverse effects of reserpine, such as
orthostatic hypotension and diarrhoea. In con-
trast to tetrabenazine, reserpine binds to VMAT1
and VMAT2 irreversibly, making the duration of
action considerably longer (hours vs days). In
addition to tetrabenazine, the two active meta-
bolites, a- and b-dihydrotetrabenazine, have
longer half-lives and are more highly bound to
proteins than the parent compound.[60-62]
The efficacy of tetrabenazine as an antichoreic
drug was convincingly demonstrated in a double-
blind, placebo-controlled trial conducted by the
Huntington Study Group.[63] Subjects were ran-
domized to receive either tetrabenazine (n = 54)
or placebo (n = 30). tetrabenazine was titrated
weekly in 12.5 mg increments to a maximum of
ª 2010 Adis Data Information BV. All rights reserved.
565
100 mg/day or the development of intolerable
adverse effects. The primary efficacy outcome
was the change from baseline in the total maximal
chorea score of the UHDRS.[37] On this scale,
chorea is graded from 0 to 4 (with 0 representing
no chorea) for seven body regions for a range in
total scores from 0 to 28. Compared with base-
line, treatment with tetrabenazine resulted in a
reduction of 5.0 units in chorea compared with a
1.5-unit reduction for those assigned to the pla-
cebo group. About 50% of tetrabenazine-treated
subjects had a 6-point or greater improvement
compared with 7% of placebo recipients. There is
also evidence to suggest continued long-term effi-
cacy and tolerability of tetrabenazine in HD.[64-67]
In the same study, the adverse events that oc-
curred significantly more frequently in the tetra-
benazine group included drowsiness/somnolence,
insomnia, depressed mood, agitation, akathisia
and hyperkinesia. However, by the conclusion of
the maintenance phase, when subjects were pre-
sumably on optimal dosage, there were no sig-
nificant differences between tetrabenazine and
placebo. Among subjects completing the study,
the most common adverse event at the end of
tetrabenazine exposure was fatigue, reported by
seven subjects on tetrabenazine (14.3%) and two
on placebo (6.9%). There was one suicide in the
double-blind study in a subject taking tetra-
benazine. Depression is common in HD and can
be exacerbated by tetrabenazine. However, sui-
cidality in HD does not necessarily correlate with
severity of depression, and may also be related to
associated impulsiveness, obsessive-compulsive
behaviour and a variety of socioeconomic
factors. Nevertheless, all patients taking tetra-
benazine need to be monitored for signs of de-
pression and suicidality. Cognition, as assessed
by the UHDRS, did not differ from that in the
placebo group statistically, although both groups
declined as expected over the course of the study.
There were no HD-related quality-of-life measures
included in the published tetrabenazine studies.
4.2 Antipsychotics
Dopamine receptor blocking agents (anti-
psychotics) are commonly considered in the
Drugs 2010; 70 (5)
566
management of chorea and psychosis in HD,
but, surprisingly, few double-blind, placebo-
controlled studies evaluating the efficacy and
safety of these agents have been published.[68-70]
None of the typical antipsychotic agents have
been found to be effective in reducing chorea in
placebo-controlled trials. However, in one study
of haloperidol in ten subjects, oral doses of
1.5–10 mg/day corresponded with at least a 30%
reduction in chorea compared with baseline.[71]
The quantity and quality of these efficacy data
need to be taken into account when considering
the risks of using typical antipsychotic agents,
particularly tardive dyskinesia. Apathy and aka-
thisia, other potential adverse effects of the
dopamine receptor blockers, can be particularly
problematic in patients with HD, as they may not
have the insight to recognize these problems or
may wrongly attribute the symptoms to HD.
Because of their presumed better tolerability,
atypical antipsychotics have been evaluated in HD
more recently. Olanzapine has been used in small
open-label studies to treat the motor symptoms of
HD.[72-76] The range of effect on chorea has been
0–66% reduction. There are no clinical trials of
risperidone for HD, but a few reports suggest
a positive effect on the disease with a tolerable
adverse-effect profile.[77-80] Quetiapine has been tried
in multiple, small, uncontrolled, nonrandomized
trials for HD with some success on both motor and
psychiatric symptoms of HD.[81-83] Clozapine was
studied in patients with HD up to a dose of
150 mg/day for up to 31 days, but many adverse
events such as drowsiness, fatigue, anticholinergic
symptoms and walking difficulties occurred with-
out beneficial effects.[84] The newer atypical agent
with multiple mechanisms of action, aripiprazole,
has been found to be beneficial in a few small trials
with a reduction in chorea equivalent to that with
tetrabenazine.[85-87] Although aripiprazole may
have fewer adverse effects on mood than tetra-
benazine, it is associated with tardive dyskinesia,
similar to other typical and atypical antipsychotics.
4.3 Other Antichorea Agents
The NMDA-antagonist amantadine has been
shown in controlled trials to significantly reduce
ª 2010 Adis Data Information BV. All rights reserved.
Frank & Jankovic
chorea in HD.[3,88] Dosages in the range of
400 mg/day or higher may be required for symp-
tomatic benefit, but even in dosages used to treat
influenza, amantadine may increase irritability
and aggressiveness.[89] Because riluzole retards
striatal glutamate release and the pathological
consequences in neurotoxic animal models of
HD, multiple large trials have been conducted to
determine if there is a possible neuroprotective
effect. Riluzole was found to reduce chorea at a
daily dose of 200 mg but not 100 mg.[90,91] Benzo-
diazepines are also frequently used clinically in
HD to treat anxiety as well as chorea and there is
limited evidence to suggest that higher dosages of
clonazepam (up to 5.5 mg/day) may be needed to
suppress chorea.[92] At this dosage, sedation
becomes a potential adverse effect. In a few short-
term studies (hours), there is evidence that do-
pamine agonists may reduce the motor signs of
HD.[93-95] Although the pharmacological ratio-
nale for using dopamine agonists in the treatment
of chorea is not clear, presumably they act by
activating the presynaptic dopamine receptors
leading to decreased dopamine turnover. How-
ever, it is more likely that the observed sympto-
matic effects are related to nonspecific or sedating
effects.
For patients with the akinetic form of HD,
such as the Westphal variant, antiparkinsonian
medications such as levodopa, dopamine ago-
nists and amantadine may be beneficial.[96-99]
Botulinum toxin injections can be also used for
focal dystonia associated with HD, including
oromandibular dystonia.[100]
5. Potential Neuroprotective and
Experimental Strategies
No known therapies slow the progression of
symptoms or change the course of HD. However,
there is suggestive evidence using various agents
that some compounds may extend life in animal
models.[101,102] There are some indications from
early human clinical trials that antioxidants and
mitochondrial enhancers such as ubidecarenone,
creatine or ethyl-eicosapentaenoic acid (ethyl-
EPA) may favourably influence the course of
disease.[103,104] Other agents hold theoretical
Drugs 2010; 70 (5)
Pharmacological Management of Huntington’s Disease
promise such as those that affect adenosine or
cannabinoid receptors.[105-107]
In a Cochrane review of the literature evalu-
ating neuroprotective strategies, eight random-
ized, double-blind, placebo-controlled clinical
trials were identified that included 1366 sub-
jects.[108] Subjects were treated for a mean 52
(range 30–144) weeks. Multiple mechanisms of
action and interventions were summarized, includ-
ing vitamin E, idebenone, baclofen, lamotrigine,
creatine, ubidecarenone/remacemide, ethyl-EPA
and riluzole. The conclusion from this meta-
analysis was that no compounds studied thus far
provided neuroprotection from advancement of
the disease, but interventions were generally safe
and well tolerated. All studies to date have used
clinical scales to measure progression of disease,
and future studies will probably need to use a
more sensitive biomarker for disease onset and
progression.
If therapies are developed to delay the pro-
gression or prevent the onset of disease, the in-
tervention will likely need to be initiated as early
in the course of the disease as possible. There is an
ongoing clinical trial to examine if high doses of
creatine can be safely tolerated in gene-positive,
asymptomatic patients.[109] However, there were
significant delays initiating this study owing to
the regulatory issues of giving an intervention to
a population without a disease. Although the re-
search participants have an expanded mutation
and will inevitably develop clinical symptoms, at
the time of enrolment they are without disease.
Administering relatively high, unstudied doses of
creatine created issues in study design. If future
interventions are going to address the underlying
pathology of cell death before the onset of clinical
disease, the FDA will need to find a way to make
it easier for drug companies to initiate and eval-
uate therapy in delayed-onset genetic disorders
such as HD. Eventually, this compound may be
used in clinical trials to determine if disease onset
can be delayed or if the disease course can be
modified by taking high doses of creatine.
Future neuroprotection strategies are likely to
be built from previously published trials and
concepts.[110] There are recently completed trials
with early evidence of promise for larger trials
ª 2010 Adis Data Information BV. All rights reserved.
567
designed to examine for delay of progression of
disease dopamine stabilizers (OSU6162 and
ACR16), ethyl-EPA and phenylbutyrate.[111-113]
Other recently completed trials have confirmed
suspicion of futility, such as with minocycline.[114]
Past trials of individual agents have failed, but the
synergy of the combination of ubidecarenone and
creatine may have promise.[115] Lithium has been
found to induce autophagy via inositol mono-
phosphatase (IMPase) inhibition, a process in-
dependent of the mammalian target of rapamycin
(mTOR)-induced autophagy, but combining it
with sirolimus (rapamycin) may be particularly
useful in the treatment of neurodegenerative dis-
eases, such as HD.[116] Fluoxetine, one of the se-
lective serotonin reuptake inhibitors, has been
also shown to stimulate CREB, increase produc-
tion of brain-derived neurotrophic factor,
enhance glycogenolysis, block voltage-gated cal-
cium and sodium channels, and decrease the
conductance of mitochondrial voltage-dependent
anion channels, and thus it may potentially exert
a neuroprotective effect in HD.[117] There are
ongoing trials of citalopram, memantine, ato-
moxetine and ramelteon, medications currently
available that have promise for symptomatic
treatment as well as neuroprotection. A new drug
in the antihistamine class, dimebolin, has been
under development for the past few years for the
cognitive aspects of HD.[118] Dimebolin is well
tolerated in short-term studies and will need to be
studied not only for its effect on cognition, but
also for its potential effects on motor and non-
motor symptoms and progression of disease.[119]
Future studies may also include older drugs de-
signed for another purpose such as methazola-
mide, since it crosses the blood-brain barrier and
is an inhibitor of cytochrome c release.[120] The
future also holds promise for the use of neurturin,
anti-huntingtin antibodies, RNA interference or
inhibition of cleavage at the caspase-6 site.[121]
Finally, as suggested by recent findings,[3] Rhes-
elicited disaggregation of mutated HTT may
account for the localized neuropathology of HD
in the striatum and to a lesser extent in the cortex;
drugs that block the binding of Rhes (and other
interacting proteins) to mutated HTT may exert
neuroprotective effects in HD.[122]
Drugs 2010; 70 (5)
568
6. Conclusions
Until clear neuroprotective strategies are
found and tested, clinicians will continue to treat
patients symptomatically. There is best evidence
for treating the chorea with tetrabenazine, but
other abnormal involuntary movements, cogni-
tion, affective disorders and behavioural dys-
control all need to be considered when choosing
therapies for patients. There is less evidence for
use of therapies in HD than for other neuro-
degenerative diseases such as Parkinson’s disease,
but well designed clinical trials continue to be
developed and implemented. There are not
enough effective, safe interventions that can be
offered to our patients and their families with this
invariably fatal disease, but there are multiple
compounds currently under investigation.
Acknowledgements
Dr Samuel Frank has received consulting fees from
Lundbeck and Allergan. Dr Joseph Jankovic is a consultant/
advisory committee member for Allergan, Inc., Michael J. Fox
Foundation for Parkinson Research, Merz Pharmaceuticals,
Lundbeck Inc. and Teva. No sources of funding were used to
assist in the preparation of this review.
References
1. The Huntington’s Disease Collaborative Research Group.
A novel gene containing a trinucleotide repeat that is ex-
panded and unstable on Huntington’s disease chromo-
somes. Cell 1993; 72 (6): 971-83
2. Nucifora Jr FC, Sasaki M, Peters MF, et al. Interference by
huntingtin and atrophin-1 with cbp-mediated transcrip-
tion leading to cellular toxicity. Science 2001; 291 (5512):
2423-8
3. Subramaniam S, Sixt KM, Barrow R, et al. Rhes, a striatal
specific protein, mediates mutant-huntingtin cytotoxicity.
Science 2009; 324 (5932): 1327-30
4. Andrich J, Saft C, Ostholt N, et al. Complex movement
behaviour and progression of Huntington’s disease.
Neurosci Lett 2007; 416 (3): 272-4
5. Frank S, Marshall F, Plumb S, et al. Functional decline due
to chorea in Huntington’s disease. Neurology 2004; 62
Suppl. 5: A204
6. Verhagen ML, Morris MJ, Farmer C, et al. Huntington’s
disease: a randomized, controlled trial using the NMDA-
antagonist amantadine. Neurology 2002; 59 (5): 694-9
7. Bates G. Huntingtin aggregation and toxicity in Hunting-
ton’s disease. Lancet 2003; 361 (9369): 1642-4
ª 2010 Adis Data Information BV. All rights reserved.
Frank & Jankovic
8. Arrasate M, Mitra S, Schweitzer ES, et al. Inclusion body
formation reduces levels of mutant huntingtin and the risk
of neuronal death. Nature 2004; 431 (7010): 805-10
9. Glass M, Dragunow M, Faull RL. The pattern of neuro-
degeneration in Huntington’s disease: a comparative
study of cannabinoid, dopamine, adenosine and
GABA(A) receptor alterations in the human basal ganglia
in Huntington’s disease. Neuroscience 2000; 97 (3): 505-19
10. Albin RL, Reiner A, Anderson KD, et al. Preferential loss
of striato-external pallidal projection neurons in pre-
symptomatic Huntington’s disease. Ann Neurol 1992;
31 (4): 425-30
11. Reiner A, Albin RL, Anderson KD, et al. Differential loss
of striatal projection neurons in Huntington disease. Proc
Natl Acad Sci U S A 1988; 85 (15): 5733-7
12. Mitchell IJ, Cooper AJ, Griffiths MR. The selective vul-
nerability of striatopallidal neurons. Prog Neurobiol
1999; 59 (6): 691-719
13. Antonini A, Leenders KL, Spiegel R, et al. Striatal glucose
metabolism and dopamine D2 receptor binding in
asymptomatic gene carriers and patients with Hunting-
ton’s disease. Brain 1996; 119 (Pt 6): 2085-95
14. Augood SJ, Faull RL, Emson PC. Dopamine D1 and D2
receptor gene expression in the striatum in Huntington’s
disease. Ann Neurol 1997; 42 (2): 215-21
15. Feigin A, Tang C, Ma Y, et al. Thalamic metabolism and
symptom onset in preclinical Huntington’s disease. Brain
2007; 130 (Pt 11): 2858-67
16. Andrews TC, Weeks RA, Turjanski N, et al. Huntington’s
disease progression. PET and clinical observations. Brain
1999; 122 (Pt 12): 2353-63
17. Weeks RA, Piccini P, Harding AE, et al. Striatal D1 and
D2 dopamine receptor loss in asymptomatic mutation
carriers of Huntington’s disease. Ann Neurol 1996; 40 (1):
49-54
18. Cha JH, Kosinski CM, Kerner JA, et al. Altered brain
neurotransmitter receptors in transgenic mice expressing a
portion of an abnormal human huntington disease gene.
Proc Natl Acad Sci U S A 1998; 95 (11): 6480-5
19. Perry TL, Hansen S, Kloster M. Huntington’s chorea.
Deficiency of gamma-aminobutyric acid in brain. N Engl
J Med 1973; 288 (7): 337-42
20. Paulsen JS. Functional imaging in Huntington’s disease.
Exp Neurol 2009; 216 (2): 272-7
21. Gourfinkel-An I, Parain K, Hartmann A, et al. Changes in
GAD67 mRNA expression evidenced by in situ hybridi-
zation in the brain of R6/2 transgenic mice. J Neuro-
chem 2003; 86 (6): 1369-78
22. Nicniocaill B, Haraldsson B, Hansson O, et al. Altered
striatal amino acid neurotransmitter release monitored
using microdialysis in R6/1 Huntington transgenic mice.
Eur J Neurosci 2001; 13 (1): 206-10
23. Harper PS. The epidemiology of Huntington’s disease.
Hum Genet 1992; 89 (4): 365-76
24. Morrison PJ, Johnston WP, Nevin NC. The epidemiology
of Huntington’s disease in Northern Ireland. J Med Genet
1995; 32 (7): 524-30
25. Peterlin B, Kobal J, Teran N, et al. Epidemiology of Hun-
tington’s disease in Slovenia. Acta Neurol Scand 2009;
119 (6): 371-5
Drugs 2010; 70 (5)
Pharmacological Management of Huntington’s Disease
26. Simpson SA, Johnston AW. The prevalence and patterns of
care of Huntington’s chorea in Grampian. Br J Psychiatry
1989; 155: 799-804
27. Penney Jr JB, Young AB, Shoulson I, et al. Huntington’s
disease in Venezuela: 7 years of follow-up on symptomatic
and asymptomatic individuals. Mov Disord 1990; 5 (2):
93-9
28. Ribai P, Nguyen K, Hahn-Barma V, et al. Psychiatric
and cognitive difficulties as indicators of juvenile hun-
tington disease onset in 29 patients. Arch Neurol 2007; 64
(6): 813-9
29. Biglan KM, Ross CA, Langbehn DR, et al., PREDICT-
HD Investigators of the Huntington Study Group. Motor
abnormalities in premanifest persons with Huntington’s
disease: the PREDICT-HD study. Mov Disord 2009 Sep
15; 24 (12): 1763-72
30. Tabrizi SJ, Langbehn DR, Leavitt BR, et al., TRACK-HD
investigators. Biological and clinical manifestations of
Huntington’s disease in the longitudinal TRACK-HD
study: cross-sectional analysis of baseline data. Lancet
Neurol 2009 Sep; 8 (9): 791-801
31. Huntington Study Group PHAROS Investigators (Shoul-
son I, primary author). At risk for Huntington’s disease:
the PHAROS (Prospective Huntington at risk observa-
tional study) cohort enrolled. Arch Neurol 2006; 63: 991-8
32. Huntington Study Group. Cooperative Huntington’s Ob-
servational Research Trial [ClinicalTrials.gov identifier
NCT00313495]. US National Institutes of Health. Clinical
Trials.gov [online]. Available from URL: http://www.clini
caltrials.gov [Accessed 2010 Jan 26]
33. Solomon AC, Stout JC, Johnson SA, et al., Predict-HD in-
vestigators of the Huntington Study Group. Verbal episodic
memory declines prior to diagnosis in Huntington’s disease.
Neuropsychologia 2007 Apr 9; 45 (8): 1767-76
34. Johnson SA, Stout JC, Solomon AC, et al., Predict-HD
Investigators of the Huntington Study Group. Beyond
disgust: impaired recognition of negative emotions prior
to diagnosis in Huntington’s disease. Brain 2007 Jul; 130
(Pt 7): 1732-44
35. Paulsen JS, Langbehn DR, Stout JC, et al., Predict-HD
Investigators and Coordinators of the Huntington Study
Group. Detection of Huntington’s disease decades before
diagnosis: the Predict-HD study. J Neurol Neurosurg
Psychiatry 2008 Aug; 79 (8): 874-80
36. Duff K, Paulsen JS, Beglinger LJ, et al., Predict-HD
Investigators of the Huntington Study Group. Psychiatric
symptoms in Huntington’s disease before diagnosis: the
Predict-HD study. Biol Psychiatry 2007 Dec 15; 62 (12):
1341-6
37. Huntington Study Group. Unified Huntington’s Disease
Rating Scale: reliability and consistency. Mov Disord
1996; 11 (2): 136-42
38. The American College of Medical Genetics/American
Society of Human Genetics Huntington Disease Genetic
Testing Working Group. ACMG/ASHG statement.
Laboratory guidelines for Huntington disease genetic
testing. Am J Hum Genet 1998; 62 (5): 1243-7
39. Andrich J, Arning L, Wieczorek S, et al. Huntington’s
disease as caused by 34 CAG repeats. Mov Disord 2008;
23 (6): 879-81
ª 2010 Adis Data Information BV. All rights reserved.
569
40. Kenney C, Powell S, Jankovic J. Autopsy-proven
Huntington’s disease with 29 trinucleotide repeats. Mov
Disord 2007; 22 (1): 127-30
41. Snell RG, MacMillan JC, Cheadle JP, et al. Relationship
between trinucleotide repeat expansion and phenotypic
variation in Huntington’s disease. Nat Genet 1993; 4 (4):
393-7
42. Di ML, Squitieri F, Napolitano G, et al. Suicide risk in
Huntington’s disease. J Med Genet 1993; 30 (4): 293-5
43. Adam OR, Jankovic J. Symptomatic treatment of
Huntington disease. Neurotherapeutics 2008; 5 (2): 181-97
44. Phillips W, Shannon KM, Barker RA. The current clinical
management of Huntington’s disease. Mov Disord 2008;
23 (11): 1491-504
45. Roze E, Saudou F, Caboche J. Pathophysiology of Hun-
tington’s disease: from huntingtin functions to potential
treatments. Curr Opin Neurol 2008; 21 (4): 497-503
46. Imarisio S, Carmichael J, Korolchuk V, et al. Huntington’s
disease: from pathology and genetics to potential thera-
pies. Biochem J 2008; 412: 191-209
47. Walker FO. Huntington’s disease. Lancet 2007; 369 (9557):
218-28
48. Jankovic J. Treatment of hyperkinetic movement dis-
orders. Lancet Neurol 2009; 8 (9): 844-56
49. Bonelli RM, Wenning GK. Pharmacological management
of Huntington’s disease: an evidence-based review. Curr
Pharm Des 2006; 12 (21): 2701-20
50. Nakamura K, Aminoff MJ. Huntington’s disease: clinical
characteristics, pathogenesis and therapies. Drugs Today
(Barc) 2007; 43 (2): 97-116
51. Handley OJ, Naji JJ, Dunnett SB, et al. Pharmaceutical,
cellular and genetic therapies for Huntington’s disease.
Clin Sci (Lond) 2006; 110 (1): 73-88
52. Bonelli RM, Hofmann P. A review of the treatment options
for Huntington’s disease. Expert Opin Pharmacother
2004; 5 (4): 767-76
53. Grimbergen YA, Roos RA. Therapeutic options for Hun-
tington’s disease. Curr Opin Investig Drugs 2003; 4 (1):
51-4
54. Bagchi SP. Differential interactions of phencyclidine
with tetrabenazine and reserpine affecting intraneuronal
dopamine. Biochem Pharmacol 1983; 32 (19): 2851-6
55. Pettibone DJ, Pflueger AB, Totaro JA. Tetrabenazine-
induced depletion of brain monoamines: mechanism by
which desmethylimipramine protects cortical norepine-
phrine. Eur J Pharmacol 1984; 102 (3-4): 431-6
56. Mehvar R, Jamali F. Concentration-effect relationships
of tetrabenazine and dihydrotetrabenazine in the rat.
J Pharm Sci 1987; 76 (6): 461-5
57. Thibaut F, Faucheux BA, Marquez J, et al. Regional dis-
tribution of monoamine vesicular uptake sites in the
mesencephalon of control subjects and patients with
Parkinson’s disease: a postmortem study using tritiated
tetrabenazine. Brain Res 1995; 692 (1-2): 233-43
58. Kenney C, Hunter C, Davidson A, et al. Short-term effects
of tetrabenazine on chorea associated with Huntington’s
disease. Mov Disord 2007; 22 (1): 10-3
59. Scherman D, Henry JP. Reserpine binding to bovine
chromaffin granule membranes. Characterization and
Drugs 2010; 70 (5)
570
comparison with dihydrotetrabenazine binding. Mol
Pharmacol 1984; 25 (1): 113-22
60. Mehvar R, Jamali F, Watson MW, et al. Pharmacokinetics
of tetrabenazine and its major metabolite in man and rat.
Bioavailability and dose dependency studies. Drug Metab
Dispos 1987; 15 (2): 250-5
61. Roberts MS, Watson HM, McLean S, et al. Determination
of therapeutic plasma concentrations of tetrabenazine and
an active metabolite by high-performance liquid chro-
matography. J Chromatogr 1981; 226 (1): 175-82
62. Roberts MS, McLean S, Millingen KS, et al. The phar-
macokinetics of tetrabenazine and its hydroxy metabolite
in patients treated for involuntary movement disorders.
Eur J Clin Pharmacol 1986; 29 (6): 703-8
63. Huntington Study Group. Tetrabenazine as antichorea
therapy in Huntington disease: a randomized controlled
trial. Neurology 2006; 66 (3): 366-72
64. Jankovic J, Beach J. Long-term effects of tetrabenazine in
hyperkinetic movement disorders. Neurology 1997; 48 (2):
358-62
65. Kenney C, Hunter C, Jankovic J. Long-term tolerability of
tetrabenazine in the treatment of hyperkinetic movement
disorders. Mov Disord 2007; 22 (2): 193-7
66. Fasano A, Cadeddu F, Guidubaldi A, et al. The long-term
effect of tetrabenazine in the management of Huntington
disease. Clin Neuropharmacol 2008; 31 (6): 313-8
67. Huntington Study Group/Tetra-HD Investigators. Tetra-
benazine as anti-chorea therapy in Huntington disease: an
open-label continuation study. BMC Neurol 2009 Dec 18;
9: 62
68. Quinn N, Marsden CD. A double blind trial of sulpiride in
Huntington’s disease and tardive dyskinesia. J Neurol
Neurosurg Psychiatry 1984; 47 (8): 844-7
69. Deroover J, Baro F, Bourguignon RP, et al. Tiapride
versus placebo: a double-blind comparative study in the
management of Huntington’s chorea. Curr Med Res Opin
1984; 9 (5): 329-38
70. Leonard DP, Kidson MA, Brown JG, et al. A double blind
trial of lithium carbonate and haloperidol in Huntington’s
chorea. Aust N Z J Psychiatry 1975; 9 (2): 115-8
71. Barr AN, Fischer JH, Koller WC, et al. Serum haloperidol
concentration and choreiform movements in Hunting-
ton’s disease. Neurology 1988; 38 (1): 84-8
72. Bonelli RM, Mahnert FA, Niederwieser G. Olanzapine for
Huntington’s disease: an open label study. Clin Neuro-
pharmacol 2002; 25 (5): 263-5
73. Bonelli RM, Niederwieser G, Tribl GG, et al. High-dose
olanzapine in Huntington’s disease. Int Clin Psycho-
pharmacol 2002; 17 (2): 91-3
74. Paleacu D, Anca M, Giladi N. Olanzapine in Huntington’s
disease. Acta Neurol Scand 2002; 105 (6): 441-4
75. Squitieri F, Cannella M, Piorcellini A, et al. Short-term
effects of olanzapine in Huntington disease. Neuro-
psychiatry Neuropsychol Behav Neurol 2001; 14 (1):
69-72
76. Dipple HC. The use of olanzapine for movement disorder
in Huntington’s disease: a first case report. J Neurol
Neurosurg Psychiatry 1999; 67 (1): 123-4
77. Cankurtaran ES, Ozalp E, Soygur H, et al. Clinical ex-
perience with risperidone and memantine in the treatment
ª 2010 Adis Data Information BV. All rights reserved.
Frank & Jankovic
of Huntington’s disease. J Natl Med Assoc 2006; 98 (8):
1353-5
78. Erdemoglu AK, Boratav C. Risperidone in chorea and
psychosis of Huntington’s disease. Eur J Neurol 2002;
9 (2): 182-3
79. Madhusoodanan S, Brenner R. Use of risperidone in psy-
chosis associated with Huntington’s disease. Am J Geriatr
Psychiatry 1998; 6 (4): 347-9
80. Parsa MA, Szigethy E, Voci JM, et al. Risperidone in
treatment of choreoathetosis of Huntington’s disease.
J Clin Psychopharmacol 1997; 17 (2): 134-5
81. Alpay M, Koroshetz WJ. Quetiapine in the treatment of
behavioral disturbances in patients with Huntington’s
disease. Psychosomatics 2006; 47 (1): 70-2
82. Seitz DP, Millson RC. Quetiapine in the management of
psychosis secondary to Huntington’s disease: a case re-
port. Can J Psychiatry 2004; 49 (6): 413
83. Bonelli RM, Niederwieser G. Quetiapine in Huntington’s
disease: a first case report. J Neurol 2002; 249 (8): 1114-5
84. van Vugt JP, Siesling S, Vergeer M, et al. Clozapine versus
placebo in Huntington’s disease: a double blind random-
ised comparative study. J Neurol Neurosurg Psychiatry
1997; 63 (1): 35-9
85. Ciammola A, Sassone J, Colciago C, et al. Aripiprazole in
the treatment of Huntington’s disease: a case series.
Neuropsychiatr Dis Treat 2009; 5: 1-4
86. Brusa L, Orlacchio A, Moschella V, et al. Treatment of the
symptoms of Huntington’s disease: preliminary results
comparing aripiprazole and tetrabenazine. Mov Disord
2009; 24 (1): 126-9
87. Lin WC, Chou YH. Aripiprazole effects on psychosis
and chorea in a patient with Huntington’s disease. Am J
Psychiatry 2008; 165 (9): 1207-8
88. Lucetti C, Gambaccini G, Bernardini S, et al. Amantadine
in Huntington’s disease: open-label video-blinded study.
Neurol Sci 2002; 23 Suppl. 2: S83-4
89. Stewart JT. Adverse behavioral effects of amantadine
therapy in Huntington’s disease. South Med J 1987; 80
(10): 1324-5
90. Dosage effects of riluzole in Huntington’s disease: a
multicenter placebo-controlled study. Neurology 2003;
61 (11): 1551-6
91. Landwehrmeyer GB, Dubois B, de Yebenes JG, et al.
Riluzole in Huntington’s disease: a 3-year, randomized
controlled study. Ann Neurol 2007; 62 (3): 262-72
92. Peiris JB, Boralessa H, Lionel ND. Clonazepam in the
treatment of choreiform activity. Med J Aust 1976; 1 (8):
225-7
93. Frattola L, Albizzati MG, Alemani A, et al. Acute treat-
ment of Huntington’s chorea with lisuride. J Neurol Sci
1983; 59 (2): 247-53
94. Vitale C, Marconi S, Di ML, et al. Short-term continuous
infusion of apomorphine hydrochloride for treatment of
Huntington’s chorea: a double blind, randomized cross-
over trial. Mov Disord 2007; 22 (16): 2359-64
95. Corsini GU, Onali P, Masala C, et al. Apomorphine hydro-
chloride-induced improvement in Huntington’s chorea:
stimulation of dopamine receptor. Arch Neurol 1978;
35 (1): 27-30
Drugs 2010; 70 (5)
Pharmacological Management of Huntington’s Disease
96. Low PA, Allsop JL, Halmagyi GM. Huntington’s chorea:
the rigid form (Westphal variant) treated with levodopa.
Med J Aust 1974; 1 (11): 393-4
97. Low PA, Allsop JL. Huntington’s chorea–the rigid form
(Westphal variant) treated with l-DOPA: a case report.
Proc Aust Assoc Neurol 1973; 10 (0): 45-6
98. Magnet MK, Bonelli RM, Kapfhammer HP. Amantadine
in the akinetic-rigid variant of Huntington’s disease. Ann
Pharmacother 2004; 38 (7-8): 1194-6
99. Bonelli RM, Niederwieser G, Diez J, et al. Pramipexole
ameliorates neurologic and psychiatric symptoms in a
Westphal variant of Huntington’s disease. Clin Neuro-
pharmacol 2002; 25 (1): 58-60
100. Tan EK, Jankovic J, Ondo W. Bruxism in Huntington’s
disease. Mov Disord 2000; 15 (1): 171-3
101. Beal MF, Ferrante RJ. Experimental therapeutics in
transgenic mouse models of Huntington’s disease. Nat
Rev Neurosci 2004; 5 (5): 373-84
102. Hersch SM, Ferrante RJ. Translating therapies for Hun-
tington’s disease from genetic animal models to clinical
trials. NeuroRx 2004; 1 (3): 298-306
103. Hersch SM, Gevorkian S, Marder K, et al. Creatine in Hun-
tington disease is safe, tolerable, bioavailable in brain and
reduces serum 8OH2’dG. Neurology 2006; 66 (2): 250-2
104. Huntington Study Group. A randomized, placebo-
controlled trial of coenzyme Q10 and remacemide in
Huntington’s disease. Neurology 2001; 57 (3): 397-404
105. Curtis A, Rickards H. Nabilone could treat chorea and
irritability in Huntington’s disease. J Neuropsychiatry
Clin Neurosci 2006; 18 (4): 553-4
106. Consroe P, Laguna J, Allender J, et al. Controlled clinical
trial of cannabidiol in Huntington’s disease. Pharmacol
Biochem Behav 1991; 40 (3): 701-8
107. Muller-Vahl KR, Schneider U, Emrich HM. Nabilone in-
creases choreatic movements in Huntington’s disease.
Mov Disord 1999; 14 (6): 1038-40
108. Mestre T, Ferreira J, Coelho MM, et al. Therapeutic
interventions for disease progression in Huntington’s dis-
ease. Cochrane Database Syst Rev 2009; (3): CD006455
109. Massachusetts General Hospital. Creatine Safety and Tol-
erability in Premanifest HD [ClinicalTrials.gov identifier
NCT00592995]. US National Institutes of Health. Clin-
ical Trials.gov [online]. Available from URL: http://
www.clinicaltrials.gov [Accessed 2010 Jan 26]
110. Hersch SM, Rosas HD. Neuroprotection for Huntington’s
disease: ready, set, slow. Neurotherapeutics 2008; 5 (2): 226-36
ª 2010 Adis Data Information BV. All rights reserved.
571
111. Tedroff J, Ekesbo A, Sonesson C, et al. Long-lasting im-
provement following (-)-OSU6162 in a patient with
Huntington’s disease. Neurology 1999; 53 (7): 1605-6
112. Huntington Study Group TREND-HD Investigators.
Randomized controlled trial of ethyl-eicosapentaenoic
acid in Huntington disease: the TREND-HD study. Arch
Neurol 2008; 65 (12): 1582-9
113. Huntington Study Group. PHEND-HD: a safety,
tolerability, and biomarker study of phenylbutyrate in
symptomatic HD [abstract]. Neurotherapeutics 2008;
5 (2): 363
114. Huntington Study Group. A phase 2 trial of minocycline
in Huntington’s disease [abstract]. Mov Disord 2009;
24 Suppl. 1: S164
115. Yang L, Calingasan NY, Wille EJ, et al. Combination
therapy with coenzyme Q10 and creatine produces ad-
ditive neuroprotective effects in models of Parkinson’s
and Huntington’s diseases. J Neurochem 2009; 109 (5):
1427-39
116. Pan T, Kondo S, Le W, et al. The role of autophagy-
lysosome pathway in neurodegeneration associated with
Parkinson’s disease. Brain 2008; 131 (Pt 8): 1969-78
117. Mostert JP, Koch MW, Heerings M, et al. Therapeutic
potential of fluoxetine in neurological disorders. CNS
Neurosci Ther 2008; 14 (2): 153-64
118. US National Institutes of Health. ClinicalTrials.gov [on-
line]. Available from URL: http://www.clinicaltrials.gov
[Accessed 2010 Jan 26]
119. Kieburtz K, McDermott MP, Voss TS, et al. A randomized,
placebo-controlled trial of latrepirdine in Huntington
disease. Arch Neurol 2010; 67 (2): 154-60
120. Wang X, Zhu S, Pei Z, et al. Inhibitors of cytochrome
c release with therapeutic potential for Huntington’s
disease. J Neurosci 2008; 28 (38): 9473-85
121. Graham RK, Deng Y, Slow EJ, et al. Cleavage at the
caspase-6 site is required for neuronal dysfunction and
degeneration due to mutant huntingtin. Cell 2006; 125 (6):
1179-91
122. Kaltenbach LS, Romero E, Becklin RR, et al. Huntingtin
interacting proteins are genetic modifiers of neurodegen-
eration. PLoS Genet 2007 May 11; 3 (5): e82
Correspondence: Dr Samuel Frank, 72 East Concord St,
Collamore 329, Boston, MA 02118, USA.
E-mail: samfrank@bu.edu
Drugs 2010; 70 (5)
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.