IOS Press The pathophysiology and pharmacological ...

Behavioural Neurology 26 (2013) 245–253 245DOI 10.3233/BEN-2012-120267IOS Press

The pathophysiology and pharmacologicaltreatment of Huntington disease

Connie Pidgeon∗ and Hugh RickardsThe Michael Trimble Neuropsychiatry Research Group, Department of Neuropsychiatry, BSMHFT and Universityof Birmingham, Birmingham, UK

Abstract. Introduction: Huntington disease (HD) is a progressive neurodegenerative condition characterised by motor, cognitiveand behavioural dysfunction, and has an autosomal dominant mode of inheritance. As there is currently no treatment to delayprogression of the disease, pharmacological intervention is aimed at symptomatic relief.Methods: We set out to assess the current evidence on the pharmacological treatment of motor and non-motor symptoms in HDby carrying out a systematic literature review across five large scientific databases.Results: The search generated 23 original studies meeting our search criteria. Studies on the following drug classes wereobtained: dopamine (DA) depleting agents, neuroleptics, anti-glutamatergic agents, acetylcholinesterase inhibitors, GABAagonists, cannabinoids, antidepressants and potential neuroprotective agents. Tetrabenazine (TBZ), a DA depleting agent, wasthe only pharmacotherapy shown to have a clinically meaningful, statistically significant effect on chorea. The majority of thereviewed studies focussed on the treatment of motor symptoms of HD.Discussion: Overall, the evidence base for the pharmacological management of HD is poor. There is a clear need for futurehigh quality randomised controlled trials on the symptomatic treatment of HD, particularly on the pharmacotherapy of non-motorsymptoms of HD.

Keywords: Chorea, dopamine, Huntington disease, non-motor symptoms, pharmacotherapy, tetrabenazine

1. Introduction

Huntington’s disease (HD) is a progressive neurode-generative conditionwhich demonstrates an autosomal-dominant mode of inheritance. HD is characterised bymotor, cognitive and behavioural dysfunction [1] andhas a prevalenceof around 4–10 per 100,000 in Westerncountries [2]. It is caused by an expanded CAG repeatin the Huntingtin gene (HTT) located on the short armof chromosome 4 at the IT15 locus, which results inan abnormal polyglutamine sequence in the huntingtinprotein (Htt) [2–4]. HD occurs when the number ofCAG repeats exceeds 36, and repeats of 40 or more re-sults in full penetrance of the disease [4]. The numberof CAG repeats is also inversely proportional to the ageof onset of symptoms at a population level [6].

∗Corresponding author: Connie Pidgeon, Department of Neu-ropsychiatry, The Barberry National Centre for Mental Health, Birm-ingham B15 2FG, UK. Tel.: +44 121 3012317; Fax: +44 1213012291; E-mail: [email protected].

The characteristic symptom of HD is chorea (ran-dom, dance-like movements) [7]. Other motor symp-toms include dystonia, problems initiating volun-tary movements, gait disturbances, tics, myoclonus,dysarthria and saccadic eye movements [7–9]. Sig-nificant cognitive and behavioural symptoms also oc-cur, such as depression, dementia, psychosis, impairedexecutive function, apathy, irritability, aggression andpersonality changes [7,8]. These symptoms often oc-cur in the early stages of the disease, before the onsetof motor symptoms [2].

The mean age of symptom onset is 40 years, al-though symptoms can begin at any age. There is alsoan early-onset form of HD (juvenile HD or Westphalvariant), defined as onset occurring before 20 years, inwhich rigidity and bradykinesia are predominant mo-tor symptoms [9]. Life expectancy after diagnosis isaround 20 years, during which time the patient maybecome fully dependent [2]. Death usually occurs bysecondary causes such as pneumonia [7], and there isalso a high incidence of suicide [9,10].

ISSN 0953-4180/13/$27.50 2013 – IOS Press and the authors. All rights reserved

246 C. Pidgeon and H. Rickards / The pathophysiology and pharmacological treatment of Huntington disease

Despite the fact that the location of the HTT genemutation was identified in 1993 [4], the pathologicalmechanism by which the Htt protein causes neuronalcell dysfunction is still poorly understood. Htt is ex-pressed in all cells, but particularly affects neurons, re-sulting in the development of toxic function [2]. Thisprotein forms aggregates or inclusion bodies that aredistributed throughout neurons and interact with oth-er proteins, leading to neuronal cell dysfunction andeventual death via a variety of possible mechanisms,including caspase activation [11], mitochondrial dys-function [12], transcriptional dysregulation [13] and in-creased sensitivity to excitotoxicity [7]. It is likely thatmore than one of these processes occur simultaneous-ly [14].

The neuropathological changes of HD are selec-tive [9]. Neurons in the striatum (a key component ofthe basal ganglia) are predominantly affected by thisprocess and this occurs early in the disease course, lead-ing to atrophy of this area of the brain [15]. Increasingnumbers of neurons in other areas are affected as thedisease progresses, eventually leading to diffuse brainatrophy [2]. The inhibitory medium spiny GABAergicneurons that project from the striatum to the globuspallidus-pars externa (GPe) are most vulnerable and arefirst affected [7]. This results in dysfunction withinthe indirect pathway of the basal ganglia which, alongwith the direct pathway, controls voluntary movement.Specifically, a decrease in the inhibitory neurotransmit-ter GABA from the striatum to the GPe results in over-inhibition of the subthalamic nucleus (STN) which, viaoutput neurons, causes less inhibition of the thalamus,resulting in an increased release of the excitatoryneuro-transmitter glutamate to the frontal cortex. The clinicalcorrelate of this pathophysiological process is chorea.Dysfunction of both the indirect and direct motor path-ways within the basal ganglia leads to the wide range ofmotor symptoms present in HD [16–18]. Other frontal-subcortical circuits that involve the basal ganglia arealso affected as neuronal loss progresses in this area.These pathways control other cognitive, behaviouraland emotional functions, therefore playing a causativerole in the non-motor symptoms of HD [19].

To date, no neuroprotective, disease-modifying orcurative treatment for HD has been developed [1]. Ac-cordingly, pharmacological intervention is aimed atsymptomatic relief [17]. The majority of pharma-cotherapy used to treat the motor symptoms is aimedat restoring the balance of neurotransmitters that areinvolved in the pathogenesis of HD, primarily GABA,dopamine (DA) and glutamate [14,20]. These include

DA depleting agents such as tetrabenazine (TBZ), DAD2 receptor antagonists (typical and atypical neurolep-tics), anti-glutamatergic agents and GABA-agonists.Dopaminergic agents such as Levodopa are sometimesused to treat rigidity and Parkinsonian symptoms, oc-curing most often in the juvenile form of HD [9].Drugs used to treat the behavioural and cognitive symp-toms include antidepressants, such as selective sero-tonin reuptake inhibitors (SSRIs), acetylcholinesteraseinhibitors (for memory problems), and neuroleptics,which can be used to treat both psychotic and motorsymptoms [1].

HD is a devastating, progressive disease with nocurrent disease-modifying treatment available. Con-sequently, it is crucial that patients receive the mostefficacious symptomatic treatment tailored to their in-dividual needs in order to improve their health-relatedquality of life. This paper aims to review the currentevidence on the efficacy of pharmacological treatmentfor the motor, behavioural and cognitive symptoms ofHD.

2. Methods

We conducted a systematic literature review accord-ing to the methodology suggested by the PRISMAguidelines [22]. Computerised literature searches wereperformed across the following five databases: MED-LINE, PsycINFO, EMBASE, Thompson Web of Sci-ence, and the Cochrane Central Register of ControlledTrials. Due to the broad scope of terminology used todescribe the symptoms of HD, two separate groups ofsearch terms were entered into each database. For bothsearches the terms ‘Huntington*’,‘drug’, ‘medication’,and ‘pharmaco*’ were used. The following searchterms were added to the first search to encompass thepharmacotherapy for the motor symptoms: ‘chorea’,‘motor’, ‘movement’, ‘dystoni*’ and ‘tic’. The searchterms ‘behav*’, ‘mood’, ‘affect’, ‘psychoses’, ‘delu-sion’, ‘cogniti*’, ‘depression’ and ‘anxi*’ were addedto the second search to find trials on the treatment ofthe behavioural (psychiatric) and cognitive (neuropsy-chological) symptoms. In addition, PsycINFO andEMBASE thesauri and the Medical Subject Heading(MeSH) database of controlled vocabularywere used toindex papers and find alternative search terms. More-over, to identify articles that did not come up in theinitial searches, the contents tables of journals that pub-lish articles relevant to this topic were reviewed. Theseincluded: Brain; The Journal of Neurology, Neuro-

C. Pidgeon and H. Rickards / The pathophysiology and pharmacological treatment of Huntington disease 247

surgery and Psychiatry; Movement Disorders; Neurol-ogy; and Clinical Neuropharmacology. The referencelists of recent review articles were scanned for furtherrelevant studies, and additional searches were carriedout in the ‘Google Scholar’ search engine. Finally, ad-vice was sought from HD experts to ensure any perti-nent articles were not overlooked.

The preliminary search generated over 2500 resultsand was subsequently limited to English language pa-pers published after 1980. Further exclusion criteriaincluded case series, case reports, editorials, commen-taries, and letters to the editors of scientific journals.Following removal of unrelated and duplicate papers,over 150 results were still eligible for inclusion. There-fore it was decided to exclude open-label and retro-spective trials, and to focus this systematic literaturereview on double-blind, randomised controlled trials(RCTs) with 20 or more patients, thereby only includ-ing RCTs with high quality evidence. As this reviewis on symptomatic treatment, studies on potential neu-roprotective treatments were only included if the mainform of assessment was the effect of the drug on HDsymptoms.

3. Results

Table 1 displays the 23RCTs on the pharmacologicaltreatment of HD that matched the criteria set out in theMethods section. All but one study [23] were placebo-controlled, further adding to the overall high-qualitynature of the studies. The study results, organised bydrug class, are discussed in the following paragraphs.

3.1. DA depleting agents

Two RCTs found TBZ to have a positive effect onreducing chorea. A multicentre study by the HSG [24]randomised patients to receive placebo (n = 30) orTBZ (n = 54) for 12 weeks. The TBZ dose startedat 12.5 mg/day and was titrated up to a maximum of100 mg/day. TBZ treatment resulted in a decline of5.0 units of chorea severity assessed by the UHDRS,compared to a decline of 1.5 units in the placebo group.A study by Frank et al. [22] randomised 30 patientswho had been taking TBZ for at least 2 months into 3groups, and who then withdrew from TBZ in a stag-gered fashion over a 5-day period. The efficacy andshort half-life of TBZ was demonstrated by a worsen-ing of chorea in the withdrawal and partial withdrawalgroups compared to the non-withdrawal group.

3.2. Neuroleptics

Both typical and atypical neuroleptics can be usedfor the treatment of chorea and psychosis in HD [20].Both are DA D2 receptor antagonists, however the new-er atypical antipsychotics are preferred because theycause less extrapyramidal side-effects [1]. Three RCTson atypical neuroleptics were found which met the in-clusion criteria of the present systematic literature re-view. Clozapine was studied by van Vugt et al in a RCTwith 33 patients [25], and was found to have little ben-eficial effect on chorea. However, a high proportion ofpatients experienced adverse effects, meaning that themaximum dose of 150 mg/day was not reached (whichcould potentially have resulted in a greater efficacy).Tiapride (dose 3g/day), a substituted benzamide, wasfound by Deroover et al. [25] to have a significant pos-itive effect on chorea in a placebo-controlled crossoverstudy of 29 patients. Conversely, a 2-week study byRoos et al. [26] in which patients took 100 mg/day oftiapride found no significant effects on chorea. How-ever, the lower dose and difference in assessment andrating scales could have contributed to the different out-comes. A recent study by Lundin et al. [27] found pri-dopidine, a dopaminergic stabiliser, to have a similareffectiveness to placebo.

3.3. Anti-glutamatergic agents

Two similar RCTs were found on amantadine (aNMDA-receptor antagonist). Both trials were of 4-weeks duration and involved 24 patients and similardoses. However, these studies have conflicting results.Verhagen-Metmanet al. [28] found 400 mg/day to havea positive effect on chorea and few adverse effects.Conversely, O’Suilleabhain and Dewey [29] showedthat amantadine 300 mg/day had no impact on choreacompared to placebo, and more adverse effects werereported. However, 19 patients reported subjective im-provement after the treatment phase, compared to 6after the placebo phase.

Remacemide is a non-competitive NMDA-receptorantagonist. In a RCT by Kieburtz et al. [30] patients re-ceiving remacemide 200 mg/day dose showed an over-all improvement in chorea level. A larger multicentrestudy involving 347 patients by the HSG [31] lookedinto the effects of remacemide and coenzyme Q10 (aneuroprotective agent) on functional decline in earlyHD. Neither medication was found to have a statisti-cally significant effect, as measured primarily by thechange in Total Functional Capacity (TFC). However,


Tabl

e1

Ran

dom

ised

cont

rolle

dtria

lson

the

phar

mac

olog

ical

trea

tmen

tofth

em

otor

and

non-

mot

orsy

mpt

omsof

Hun

tingt

ondi

seas

e

Stud

yC

ount

ryTre

atm

ent

Stud

yn

Med

icat

ion

Mec

hani

smPr

imar

yO

vera

llC

onco

mita

ntdu

ratio

nde

sign

ofac

tion

outc

ome

effic

acy

HD

mea

sure

(s)

(Com

pare

dto

med

icat

ion

plac

ebo)

Fran

ket

al.

(200

8)[2

3]∗

USA

5da

ysPa

ralle

l30

TB

ZD

opam

ine

depl

etin

gag

ent

UH

DR

SG

ood

Not

cont

rolle

d

HSG

(200

6)[2

4]U

SA12

wee

ksPa

ralle

l84

TB

ZD

opam

ine

depl

etin

gag

ent

UH

DR

SG

ood

Con

trol

led

and

perm

itted

med

-ic

atio

nw

aske

ptco

nsta

ntva

nVug

teta

l.(1

997)

[25]

Hol

land

31da

ysPa

ralle

l33

Clo

zapi

neD

2re

cept

oran

tago

nist

UH

DR

S,A

IMS

Poor

Kep

tcon

stan

t

Der

oove

ret

al.

(198

4)[2

6]B

elgi

um9

wee

ksC

ross

-ove

r29

Tia

prid

eD

2re

cept

oran

tago

nist

Cho

rea-

scal

ean

dm

otor

activ

ity-

scal

e,su

bjec

tive

mea

sure

men

tsof

anxi

ety

Goo

dC

ontrol

led

–on

lyan

xiol

ytic

san

dan

tidep

ress

ants

allo

wed

Roo

set

al.

(198

2)[2

7]D

enm

ark

4w

eeks

Cro

ss-o

ver

22Tia

prid

eD

2re

cept

oran

tago

nist

chor

easc

ale

(+su

bjec

tive)

Non

eK

eptc

onst

ant

Lun

din

etal

.(2

010)

[28]

Swed

enan

dN

orw

ay4

wee

ksPa

ralle

l58

Prid

opid

ine

(AC

R16

)D

opam

iner

gic

stab

ilise

rW

eigh

ted

cogn

itive

scor

eN

one

Kep

tcon

stan

t

Ver

hage

n-M

etm

anet

al.(2

002)

[29]

USA

4w

eeks

Cro

ss-o

ver

24A

man

tadi

neN

MD

A-r

ecep

tor

anta

goni

stU

HD

RS

Goo

dN

otal

low

ed

O’S

uille

abha

inan

dD

ewey

(200

3)[3

0]

USA

2w

eeks

Cro

ss-o

ver

24A

man

tadi

neN

MD

A-r

ecep

tor

anta

goni

stC

hore

a-sc

ale

(vid

eo)

Non

eK

eptc

onst

ant

Kie

burtz

etal

.(1

996)

[31]

USA

5w

eeks

Para

llel

31R

emac

emid

eN

MD

A-r

ecep

tor

anta

goni

stH

DFC

S,H

DM

RS

and

TFC

Poor

Con

trol

led

and

kept

cons

tant

HSG

(200

1)[3

2]U

SA30

mon

ths

Para

llel

347

Rem

acem

ide

NM

DA

-rec

epto

rTFC

Poor

Not

cont

rolle

d(o

ther

than

Coe

nzym

eQ

10

anta

goni

stA

ntio

xida

ntPo

orex

clud

edif

take

nC

oenz

yme

Q10

inpr

eced

ing

3m

onth

s)Lan

dweh

rmey

eret

al.

(200

7)[3

3]8

Eur

opea

nC

ount

ries

3ye

ars

Para

llel

537

Rilu

zole

Inhi

bits

glut

amat

ere

leas

eU

HD

RS

Non

eN

otal

low

ed

HSG

(200

3)[3

4]U

SAan

dC

anad

a8

wee

ksPa

ralle

l63

Rilu

zole

Inhi

bits

glut

amat

ere

leas

eU

HD

RS

Goo

dK

eptc

onst

ant

Kre

mer

etal

.(1

999)

[35]

Can

ada

30m

onth

sPa

ralle

l64

Lam

otrigi

neIn

hibi

tsgl

utam

ate

rele

ase

TFC

,QN

EPo

orC

ontrol

led

Cub

oet

al.

(200

6)[3

6]U

SAan

dSp

ain

12w

eeks

Para

llel

30D

onep

ezil

Ace

tylc

holin

erst

erar

e-in

hibi

tor

UH

DR

S,A

DA

SN

one

Con

trol

led

Shou

lson

etal

.(1

989)

[37]

USA

42m

onth

sPa

ralle

l60

Bac

lofe

nG

ABA

agon

ist

TFC

Non

eN

otco

ntro

lled

Cur

tiset

al.

(200

9)[3

8]U

K15

wee

ksC

ross

-ove

r44

Nab

ilone

Can

nabi

noid

CB

1an

dC

B2

rece

ptor

agon

ist

UH

DR

SPo

orK

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onst

ant


Tabl

e1,

cont

inue

d

Stud

yC

ount

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Stud

yn

Med

icat

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hani

smPr

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onco

mita

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nde

sign

ofac

tion

outc

ome

effic

acy

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mea

sure

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(Com

pare

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med

icat

ion

plac

ebo)

Com

oet

al.

(199

7)[3

9]U

SA4

mon

ths

Para

llel

30Fl

uoxe

tine

Sele

ctiv

ese

roto

nin

re-u

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hibi

tor

TFC

Non

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ontrol

led

–an

tidep

ress

ants

not

allo

wed

,ot

hers

kept

cons

tant

Puri

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.(2

005)

[40]

UK

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,C

anad

a,A

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ia

1ye

arPa

ralle

l13

5Eth

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PAVar

ious

–ta

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sm

itoch

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ialfu

nctio

nU

HD

RS

Non

eN

otco

ntro

lled

(but

chan

ges

wer

eno

ted)

HSG

(200

8)[4

1]U

SAan

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mon

ths

Para

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316

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yl-E

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–ta

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Beg

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(200

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=To

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MM

SE=

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min

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n;Q

NE

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rolo

gica

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min

atio

n;A

DA

S=

Alz

heim

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Dis

ease

Ass

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entS

cale

;sub

ject

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=no

n-va

lidat

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ting

scal

e;vi

deo

=vi

deo-

blin

ded

ratin

g;*N

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aceb

o-co

ntro

lled.


the results may have been influenced by concomitantHD medication, as this was not controlled.

Riluzole is a glutamate release inhibitor. Twodouble-blind,placebo-controlledRCTswere found thatinvestigate its effect on chorea in HD. In a large studyby Landwehrmeyer et al. [32], 537 patients were ran-domised to receive riluzole 50 mg/day or placebo in a2:1 format over 3 years. Use of other antichoreic medi-cation was not permitted, adding to the study’s reliabil-ity. Whilst only 71% of patients completed the trial, themain reason for this was withdrawal due to concomi-tant medication, rather than adverse effects. No bene-ficial effects on chorea were found. The dosage effectsof riluzole were investigated in a smaller study of 63patients by the HSG [33], with contrasting results tothe previous study. After 8 weeks of treatment, riluzole200 mg/day reduced chorea compared to placebo. Fi-nally, Kremer et al. [34] conducted a RCT of lamotrig-ine, which showed improvement of chorea in the activearm and a patient-reported improvement in symptoms,although these were not statistically significant.

3.4. Acetylcholinesterase inhibitors

Acetylcholinesterase inhibitors are used to treat cog-nitive decline, a common symptom of HD. A placebo-controlled trial of 30 patients by Cubo et al. [35] foundthat donepezil was ineffective in improving either mo-tor or cognitive dysfunction in HD.

3.5. GABA agonists

Baclofen was studied in a RCT involving 60 patientsby Shoulson et al. [36], showing no benefit over place-bo.

3.6. Cannabinoids

One pilot RCT by Curtis et al. [37] focused onnabilone, a cannabinoid agent that is agonistic at bothCB1 and CB2 receptors. In this cross-over pilot trial,44 patients were randomised to receive nabilone 1 or2 mg, or placebo over a period of 15 weeks. Therewas no improvement in the nabilone arm on the pri-mary outcome measure (total motor score on the UH-DRS). However, there was some improvement in thesecondary neuropsychiatric outcomemeasures, such asirritability? (chorea and irritability I think).

3.7. Antidepressants

In a 4 month study by Como et al. [38], 30 non-depressed HD patients were randomised to either flu-

oxetine or placebo to test if fluoxetine has any clini-cal benefit for non-depressed patients. Outcome mea-sures included change in TFC, as well as in other rat-ing scales of cognitive, behavioural and neurologicalchanges. Fluoxetine was not found to significantly im-prove these symptoms, although there was a small re-duction in agitation in the treatment arm. No RCTswere found on the treatment of depression in HD pa-tients.

3.8. Potential neuroprotective agents

Two large, multicentre RCTs were found on ethyl-EPA. Both trials (Puri et al. [39] and HSG [40]) foundthat ethyl-EPA did not have a greater efficacy thanplacebo.

Other neuroprotective agents that have been tested inRCTs include atomoxetine (Beglinger et al. [41]), cre-atine (Verbessem et al. [42]), and modafinil (Blackwellet al. [43]) for cognitive dysfunction, and latrepirdine(Kieburtz et al. [44]) for cognitive, behavioural andmo-tor symptoms. No beneficial effects of atomoxetine orcreatine were reported, and modafinil and latrepirdinehad only minor positive effects.

4. Discussion

This paper systematically reviewed the current liter-ature on the symptomatic treatment of HD. Searchesacross 5 databases generated over 2500 results. Theend result after the limits and exclusion criteria wereappliedwas 23 double-blindRCTs,with all but one [23]being placebo-controlled. Due to the strict exclusioncriteria, the studies included in this paper were of thehighest quality evidence available on this topic. Themain result of this paper is that, out of the 23 RCTs, theDA-depleting agent TBZ is the pharmacological agentwith the greatest evidence base for improving the motorsymptoms of HD.

TBZ was the only pharmacotherapy shown to havea clinically meaningful, statistically significant benefiton chorea. However, in the HSG study [24] serious ad-verse events occurred exclusively in the active arm, andthese patients had worse scores in functional outcome.In clinical situations, these factors should be weighedup against its benefit in reducing chorea. Neurolepticsare used clinically to treat both chorea and psychoses,but the three studies on neuroleptics [25–27] showed noconclusive evidence for any beneficial effect on chorea.Also, none of these three studies looked into the ef-


fect on psychoses. The drug class with the greatestnumber of RCTs found was anti-glutaminergic agents.Two studies on amantadine [29,30] had conflicting re-sults in terms of the effect on chorea; this differencein outcome could be due to the relatively small samplesizes, or differences in baseline characteristics. For ex-ample, there was a considerable difference in averageage between the two cohorts. Remacemide [31] wasshown to have some beneficial effect on chorea in oneRCT. The efficacy of riluzole on reducing chorea wasdemonstrated at a dose of 200 mg/day, however thiswas associated with a considerable level of hepatic tox-icity [34], suggesting it should not be used clinically atthis dose. Nabilone [38] was found to have a beneficialimpact on neuropsychiatric symptoms, an importantfinding considering the high prevalence and severity ofthese symptoms in HD. No other medications had anysignificant positive effect on the symptoms of HD.

The difference in number between the 2500 initialsearch results and the 23 RCTs that were included inthis review shows that the symptomatic treatment ofHDis based overall on low-quality evidence from differenttypes of studies, such as case reports, case series andopen-label studies. Some drugs, for example levodopa,were not included in this review as there were no trialsthat matched the search criteria. This illustrates thescarcity of high-quality evidence for some HD medica-tions. The reason that there are few high-quality trialsmay be related to the fact that HD is a rare condition,making it difficult to recruit enough patients to achievehigh statistical power. Also, the nature of HD symp-toms may increase the likelihood of patients droppingout of studies, and may affect compliance with studyprotocols.

The majority of the reviewed studies were on mo-tor function in HD, perhaps because changes in thesesymptoms are easier to measure objectively comparedto assessing changes in behavioural and cognitivesymptoms. This is an important finding, as it is of-ten non-motor symptoms that have the greatest impacton a patient’s health-related quality of life [46]. Fur-thermore, suicide is common in HD [1,8,9]. Hence,it is crucial that any behavioural symptoms that mightmake suicide more likely are treated as effectively andefficiently as possible.

The majority of trials used objective measurementsto determine the effect of symptomatic treatment. Forexample, 9 studies used changes to the UHDRS as theirprimary outcome measure. This is usually perceivedto be beneficial, as it increases the overall reliabilityand consistency of the results. However, perhaps sub-

jective measurements such as patient-reported scalesof well-being are more important than clinician-judgedoutcomes. To illustrate this, previous studies have sug-gested that objective improvement in chorea may notcorrelate with an improvement in a patient’s mood orfunction [34].

Although this review only included trials with thehighest level of evidence available on this topic, thereare still several shortcomings which need to be ad-dressed. Firstly, over 50% of the studies had a fairlysmall sample size (n < 50). Secondly, the use of con-comitantmedicationwas not controlled in 6 of the stud-ies, which could have had a significant effect on treat-ment outcome. In addition, not all studies stated thebaseline characteristics of the patients before startingtreatment, which may have meant the two arms weredifferent from the start. In two studies the patients wererecruited by advertisements, and in several studies thepatients were recruited from specialist clinics, both ofwhich will have led to a degree of sampling bias. Insome studies a substantial number of patients were lostto follow up, possibly leading to further bias. Further-more, there was a large variation in study duration, andmedicationsmay not have had an effect within the shortduration of some studies. A particular difficulty in in-terpreting results is the difference in outcome measures,as some studies used standardised methods such as theUHDRS and were therefore easy to compare, whereasothers used self-report or subjective rating scales.

There is a clear need for more high quality, placebo-controlled, double-blind RCTs in the future on thesymptomatic treatment of HD. Further trials are neededwith a large number of patients (ideally n > 100 to en-sure adequate statistical power), and with a prolongedduration to ensure that the treatment effects are notoverlooked. It is also important to ensure that concomi-tant HD medication is controlled, and that outcomemeasures are sensitive and comparable across studies.Additionally, it is vital that more RCTs are carried outon the treatment of non-motor symptoms of HD, ofwhich there is a clear deficiency in the literature.

5. Conclusion

The aim of this paper was to systematically reviewthe available literature on the pharmacological treat-ment of symptoms in HD. Our extensive literaturesearch and strict exclusion criteria meant that only highquality RCTs were included. Despite this, the evi-dence base for the pharmacologicalmanagementof HD


is poor. Only one medication, TBZ, was consistentlyshown to have significant efficacy in the treatment ofchorea. The evidence for the treatment of behaviouraland cognitive symptoms was especially poor, empha-sised by the low number of RCTs on these symptoms.Based on these results, no definite treatment recommen-dations can be made. The results suggest that symp-tomatic intervention in HD is based more on the expe-rience and knowledge of the clinician, as opposed torigorous evidence provided by the literature [46]. Aspatients with HD are treated with medications that havevery little evidence for their effectiveness, the deci-sion to treat patients with pharmacotherapy should takeinto consideration multiple factors. Clinicians work-ing with patients with HD should always keep in mindthe importance of supportive care and management bythe multi-disciplinary team when considering treatmentoptions.

References

[1] O.R. Adam and J. Jankovic, Symptomatic treatment of Hunt-ington disease, Neurotherapeutics 5 (2008), 181–197.

[2] C.A. Ross and S.J. Tabrizi, Huntington’s disease: from molec-ular pathogenesis to clinical treatment, Lancet Neurol 10(2011), 83–98.

[3] J.F. Gusella, N.S. Wexler, P.M. Conneally, S.L. Naylor, M.A.Anderson, R.E. Tanzi et al., A polymporphic DNA markergenetically linker to Huntington’s disease, Nature 306 (1983),234–238.

[4] The Huntington’s Disease Collaborative Research Group. Anovel gene containing a trinucleotide repeat that is expandedand unstable on Huntington’s disease chromosomes, Cell 72(1993), 971–983.

[5] W. Philips, K.M. Shannon and R.A. Barker, The current clin-ical management of Huntington’s disease, Mov Disord 23(2008), 1491–1504.

[6] S.J. Tabrizi, D.R. Langbehn, B.R. Leavitt, R.A.C. Roos, A.Durr, D. Crauford et al., Biological and clinical manifesta-tions of Huntington’s disease in the longitudinal TRACK-HDstudy: cross sectional analysis of baseline data, Lancet Neurol8 (2009), 791–801.

[7] C. Wider and R. Luthi-Carter, Huntington’s disease: clinicaland aetiological aspects, Schweiz Arch Neurol Psychiatr 157(2006), 378–383.

[8] B.A. Haskins and M.B. Harrison, Huntington’s disease, CurrTreat Option N 2 (2000), 243–262.

[9] F.O. Walker, Huntington’s disease, Lancet 369 (2007), 218–228.

[10] D. Paleacu, Tetrabenazine in the treatment of Huntington’sdisease, Neuropsychiatr Dis Treat 3 (2007), 545–551.

[11] S. Krobitsch and A.G. Kazantsev, Huntington’s disease: frommolecular basis to therapeutic advances, Int J Biochem Cell B43 (2010), 20–24.

[12] J.T. Greenamyre, Huntington’s disease – making connections,N Engl J Med 365 (2007), 518–529.

[13] E. Roze, F. Saudou and J. Caboche, Pathophysiology of Hunt-ington’s disease: from huntingtin functions to potential treat-ment, Curr Opin Neurol 21 (2008), 497–503.

[14] S. Frank, Tetrabenazine: the first approved drug for the treat-ment if chorea in US patients with Huntington disease, Neu-ropsychiatr Dis Treat 6 (2010), 657–665.

[15] H. Ryu, H.D. Rosas, S.M. Hersch and R.J. Ferrante, The ther-apeutic role of creatine in Huntington’s disease, PharmacolTherapeut 108 (2005), 193–207.

[16] S. Tekin and J.L. Cummings, Frontal-subcortical neuronal cir-cuits and clinical neuropsychiatry: an update, J PsychosomRes 53 (2002), 647–654.

[17] J.P.P. van Vugt and R.A.C. Roos, Huntington’s disease: op-tions for controlling symptoms, CNS Drugs 11 (1999), 105–123.

[18] V.M. Andre, C. Cepeda and M. Levine, Dopamine and gluta-mate in Huntington’s disease: a balancing act, CNS NeurosciTher 16 (2010), 163–178.

[19] R.M.Bonelli and J.L. Cummings, Frontal-subcortical circuitryand behaviour, Dialogues Clin Neurosci 9 (2007), 141–151.

[20] R. Bonelli and P. Hofmann, A systematic review of the treat-ment studies in Huntington’s disease since 1990, Expert OpinPharmacother 7 (2007), 1–13.

[21] D. Moher, A. Liberati, J. Tetzlaff and D.G. Altman, Preferredreporting items for systematic reviews and meta-analyses: thePRISMA statement, Ann Intern Med 151 (2009), 264–269.

[22] S. Frank, W. Ondo, S. Fabn, C. Hunter, D. Oakes, S. Plumbet al., A study of chorea after tetrabenazine withdrawal inpatients with Huntington’s disease, Clin Neuropharmacol 31(2008), 127–133.

[23] Huntington Study Group, Tetrabenazine as antichorea therapyin Huntington disease: a randomised control trial, Neurology66 (2006), 366–372.

[24] J.P.P. van Vugt, S. Siesling, M. Vergeer, E.A. van der Velde andR.A.C. Roos, Clozapine versus placebo in Huntington’s dis-ease: a double blind randomised comparative study, J NeurolNeurosurg Psychiatry 63 (1997), 35–39.

[25] J. Deroover, F. Baro, R.P. Bourguignon and P. Smets, Tiaprideversus placebo: a double-blind comparative study in the man-agement of Huntington’s chorea, Curr Med Res Opin 9 (1984),329–338.

[26] R.A.C. Roos, O.J.S. Buruma, G.W. Bruyn, B. Kemp and E.A.van de Velde, Tiapride in the treatment of Huntington’s chorea,Acta Neurol Scand 65 (1982), 45–50.

[27] A. Lundin, E. Dietrichs, S. Haghighi, M.L. Goller, A. Heiberg,G. Loutfi et al., Efficacy and safety of the dopaminergic stabi-lizer pridopidine (ACR16) in patients with Huntington’s dis-ease, Clin Neuropharm 33 (2010), 260–264.

[28] L. Verhagen-Metman, M.J. Morris, C. Farmer, N.P. Gillespie,K. Mosby, J. Wuu et al., Huntington’s disease: a randomised,controlled trial using the NMDA-antagonist amantadine, Neu-rology 59 (2002), 694–699.

[29] P. O’Suilleabhain and R.B. Dewey, A randomised trial ofamantadine in Huntington disease, Arch Neurol 60 (2003),996–998.

[30] K. Kieburtz, A. Feigin, M. McDermott, P. Como, D. Adwen-der, C. Zimmerman et al., A controlled trial of remacemidehydrochloride in Huntington’s disease, Mov Disord 11 (1996),273–277.

[31] Huntington Study Group, A randomized, placebo-controlledtrial of coenzyme Q10 and remacemide in Huntington’s dis-ease, Neurology 57 (2001), 397–404.

[32] G.B. Landwehrmeyer, B. Dubois, J.G. de Yebenes, B. Kremer,W. Gaus, P.H. Kraus et al., Riluzole in Huntington’s disease:a 3-year, randomised controlled study, Ann Neurol 62 (2007),262–272.


[33] Huntington Study Group, Dosage effects if riluzole in Hunt-ington’s disease: a multicentre placebo-controlled study, Neu-rology 61 (2003), 1551–1556.

[34] B. Kremer, C.M. Clark, E.W. Almqvist, L.A. Raymond, P.Graf, C. Jacova et al., Influence of lamotrigine on progressionof early Huntington’s disease: a randomized clinical trial,Neurology 53 (1999), 1000–1011.

[35] E. Cubo, K.M. Shannon, D. Tracy, J.A. Jaglin, B.A. Bernard, J.Wuu et al., Effect of donepezil on motor and cognitive functionin Huntington disease, Neurology 67 (2006), 1268–1271.

[36] I. Shoulson, C. Odoroff, D. Oakes, J. Behr, D. Goldblatt, E.Caine et al., A controlled clinical trial of baclofen as protectivetherapy in early Huntington’s disease, Ann Neurol 25 (1989),252–259.

[37] A. Curtis, I. Mitchell, S. Patel, N. Ives and H. Rickards, Apilot study using nabilone for symptomatic treatment in Hunt-ington’s disease, Mov Disord 24 (2009), 2254–2259.

[38] P.G. Como, A.J. Rubin, C.F. O’Brien, K. Lawler, C. Hickey,A.E. Rubin et al., A controlled trial of fluoxetine in nonde-pressed patients with Huntington’s disease, Mov Disord 12(1997), 397–401.

[39] B.K. Puri, B.R. Leavitt, M.R. Hayden, C.A. Ross, A. Rosen-blatt, J.T. Greenamyre et al., Ethyl-EPA in Huntington’s dis-ease: a double-blind, randomized, placebo-controlled trial,Neurology 65 (2005), 286–292.

[40] Huntington Study Group TREND-HD Investigators. Random-ized controlled trial of ethyl-eicosapentaenoic acid in Hunt-ington disease, Arch Neurol 65 (2008), 1582–1589.

[41] L.J. Beglinger, W.H. Adams, H. Paulson, J.G. Fiedorowicz,D.R. Langbehn, K. Duff et al., Randomised controlled trialof atomoxetine for cognitive dysfunction in early Huntingtondisease, J Clin Psychopharmacol 29 (2009), 484–487.

[42] P. Verbessem, J. Lemiere, B.O. Eijnde, S. Swinnen, L. Van-hees, M. van Leemputte et al., Creatine supplementation inHuntington’s disease: a placebo-controlled pilot trial, Neurol-ogy 61 (2003), 925–930.

[43] A.D. Blackwell, N.S. Paterson, R.A. Barker, T.W. Robbinsand B.J. Sahakian, The effects of modafinil on mood andcognition in Huntington’s disease, Psychopharmacology 199(2008), 29–36.

[44] K. Kieburtz, M.P. McDermott, T.S. Voss, J. Corey-Bloom,L.M. Deuel, R. Dorsey et al., A randomized, placebo-controlled trial of latrepirdine in Huntington disease, ArchNeurol 67 (2010), 154–160.

[45] E. van Duijn, Treatment of irritability in Huntington’s disease,Curr Treat Option Neurol 12 (2010), 424–433.

[46] R.M. Bonelli and G.K. Wenning, Pharmacological manage-ment of Huntington’s disease: and evidence-based review,Curr Pharm Des 12 (2006), 2701–2720.

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