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Articles
What evidence there is for the drug
treatment of Huntington’s disease
Elizabeth Bevan and Carol Paton searched Medline, EMBASE and the Cochrane Library for evidence up to September 2006 and, in this article,
they review the literature on the pharmacological management of chorea and the psychiatric co-morbidity in patients with Huntington’s disease
untington’s disease (HD) is a
Choreiform movements are
hereditary disease that involves
often more distressing for carers and
slow progressive degeneration
health care professionals than they
of the neurones in the basal ganglia
are for patients and it should not be
and cerebral cortex. It is an autosoassumed that intervention is always
mal dominant disease caused by a
in a patient’s best interest. If chormutation of a gene on chromosome
eiform movements are problematic,
4; there is an expansion of a trinuthe use of a small dose of a typical
cleotide repeat within the part
antipsychotic such as haloperidol is
of this gene that encodes the
established clinical practice.4 There
is limited information available
Huntington protein. Neurones are
about the use of atypical antipsydamaged when the mutated protein
chotics for chorea. Two open pilot
aggregates and interferes with norstudies used olanzapine 5mg/day
mal metabolism and functioning
without success but a third open
but the mechanism is poorly underpilot study using olanzapine
stood, making it difficult to develop
30mg/day reported significantly
drugs that slow or stop progression.1
In western Europe the prevalence
improved motor function.5–7 There
of HD is between three and seven
are also anecdotal case reports to
per 100,000.2
suggest risperidone and quetiapine
Symptom onset is usually bemay be helpful.8,9
Several case reports suggest that
tween the ages of 35 and 50 years,
moderate doses of risperidone (6mg)
but can occur in early childhood or
are needed to have a significant effect
old age. The greater the number of
on motor disability.8 However, other
trinucleotide repeats, the earlier the
case reports support lower doses
age of onset. HD usually has a
(1mg twice daily) of risperidone in
course of 15 to 20 years, although
the treatment of chorea.10 It is, therejuvenile onset cases often progress
fore, unclear if higher doses of atypimore rapidly. The clinical presentacal antipsychotics may be required to
tion is characterised by increasingly
achieve an optimal response in
severe involuntary movements
chorea, but these should be consid(chorea) and cognitive decline.
ered if lower doses produce a subChoreiform movements and deoptimal response.
mentia are core symptoms of HD
Tetrabenazine, a dopamineand both psychosis and depression
depleting drug, is effective in treatare common. The cause of death is
ing moderate to severe choreiform
usually respiratory infection secmovements. Efficacy is supported by
ondary to failure of the gag reflex Huntington’s patients suffer degeneration of the basal
ganglia of the brain, which leads to jerky and involuntary
double-blind placebo-controlled
and respiratory muscles.
crossover trials.11,12 However, up to
Evidence supporting the phar- movements (chorea) and dementia
80 per cent of patients experience
macological management of chorea
and the psychiatric manifestations of HD is prominent in the early stages of the disease adverse effects, including sedation, insomnia,
summarised below. Adjuvant psychotherapy, while other movement disorders, such as dys- pseudoparkinsonism, depression, anxiety and
physiotherapy and speech therapy should be tonia, bradykinesia and rigidity, become more akathisia. Serious side effects, such as neuroleptic malignant syndrome and dysphagia
applied to provide optimal management.The prominent as the disease progresses.3
The first intervention in mild chorea leading to death from aspiration pneumonia,
use of these strategies is outside the scope of
should always be to discontinue drugs that have also been reported.13,14 The decision to
this review.
have the potential to exacerbate symptoms. treat chorea with tetrabenazine must be balChorea
Examples include piracetam and dopamine anced against the added risk of developing
Choreiform movements occur in approxi- agonists, such as levodopa, amantadine and parkinsonism and depression, both of which
mately 90 per cent of patients. Chorea is most cabergoline.3 There are no published data per- are already common in HD.3
Levetiracetam also showed some benefit in
taining to psychotropic drugs that can
Elizabeth Bevan, MPharm, MRPharmS, is increase dopaminergic neurotransmission, reducing choreiform movements in a small
a clinical pharmacist and Carol Paton,
such as aripiprazole and venlafaxine. These short-term study.15
Hypokinetic rigidity (decreased motor
MCMHP, MRPharmS, is chief pharmacist,
drugs should be considered as potential causes
both at Oxleas NHS Foundation Trust.
of exacerbations in dyskinetic movements function leading to stiffness) can occur indeCorrespondence to: Elizabeth.Bevan@
and their use is probably best avoided, at least pendently of antipsychotic medication in patients with HD.Treatment strategies are similar
oxleas.nhs.uk
as first-line treatments.
Conor Caffrey/Science Photo Library
H
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25 November 2006 The Pharmaceutical Journal (Vol 277) 641
Articles
to those used in Parkinson’s disease although
patients with HD usually respond less well.
Anticholinergics, levodopa and dopamine
agonists are used but these drugs all have the
potential to worsen chorea and precipitate
psychosis. Dosage adjustment is often
required to obtain the best balance between
efficacy and side effects. Muscle relaxants,
such as diazepam can also be effective in
treating rigidity and are usually well tolerated, although aspiration secondary to sedation is a potential risk.3
Psychosis, depression and dementia
It is estimated that between 23 and 73 per
cent of patients with HD develop depression,
psychosis or dementia during the course of
their illness.16 Such patients are likely to be
referred to a psychiatrist for advice and management but few psychiatrists see enough
cases to build up expertise in this area of
practice.
Psychosis Approximately 23 per cent of patients with HD will develop psychotic symptoms.17 These tend to present early in the
course of the illness and ameliorate as cognitive function deteriorates. Early neuropathological changes include atrophy of the medial
caudate.4 Neurotransmitter changes are complex but include a reduction in gammaaminobutyric acid and acetylcholine and an
increase in glutamatergic activity. The net
result appears to be a hyperdopaminergic
state.16 It follows that antipsychotic drugs are
likely to be effective. Case reports and case
series show the benefit of individual agents
but no randomised controlled trials have been
conducted.
The use of antipsychotic drugs in HD
psychosis is complicated by the risk of exacerbating the underlying movement disorder.
Some evidence supports the efficacy of typical antipsychotics, particularly haloperidol,
when the HD is mild to moderate.4 As the
disease progresses, typical antipsychotics tend
to be poorly tolerated due to dystonia and
parkinsonism.4 Atypical antipsychotics tend
to be used at this point although the evidence
to support their efficacy and tolerability is
also limited to case reports and series. Meco
et al18 compared risperidone with haloperidol
in three patients with HD and found that
risperidone was comparable to haloperidol in
two patients (and superior to haloperidol in
the other patient) in reducing both dyskinesia and psychotic symptoms. Additional case
reports support the efficacy of risperidone,8,19
quetiapine17 and amisulpride,20 although
extrapyramidal side effects can be problematic with all of these drugs.
Depression Depression is common in HD.
Estimates of the point prevalence range from
9 to 63 per cent but the true rate is probably
between 40 and 50 per cent.21 The suicide
rate is four to six times higher than in people
without HD.4 Suicide among patients diagnosed with HD tends to occur early in the
course of illness. It has been suggested that
642
The Pharmaceutical Journal (Vol 277) 25 November 2006
this reflects the occurrence of suicide before
motor skills decline to the point where the
person is no longer physically able to take his
or her own life.22
There are no randomised controlled trials
to guide treatment choice. Case reports of
successful treatment with tricyclic antidepressants (TCAs), monoamine oxidase inhibitors
(MAOIs), mirtazepine,23 and selective serotonin reuptake inhibitors (SSRIs) have been
published. Patients with HD seem to be particularly prone to the side effects that are
commonly associated with the TCAs, namely
sedation, falls and anticholinergic-induced
cognitive impairment.
MAOIs are also potentially problematic
because they can worsen choreiform movements, possibly through their effects on
dopamine neurotransmission.There has been
almost no new primary literature in this area
over the past 20 years.The use of SSRIs tends
to be favoured because these drugs may also
reduce the irritability and apathy that are
commonly seen in HD.24 The choice of SSRI
is not affected by the patient having HD.25
Electroconvulsive therapy seems to be relatively well tolerated in HD patients.4
Reviews state that lithium is best avoided;
clinical experience suggests that response is
likely to be poor and that toxic effects can be
particularly problematic.4 There is no primary
literature.
Dementia Almost all patients with HD
develop subcortical dementia. Patients in the
later stages of the disease tend to have profound dementia.1,2 No robust data could be
found on the use of cholinesterase inhibitors
to treat dementia in HD.There are, however,
some data to suggest that galantamine can be
used to regulate mood and behaviour, thus
improving some of the psychotic features
associated with HD. It is thought that this
occurs through allosteric modulation of nicotinic acetylcholine receptors.16 There is no
reason to suspect that the efficacy and tolerability of cholinesterase inhibitors would be
any different in HD patients than in those
with Alzheimer’s disease.
Summary
With the exception of tetrabenazine which is
used to treat choreiform movements, no
placebo controlled or randomised controlled
trials were identified. The literature consists
entirely of case reports and case series. Most
are old and treatment is largely empirical.
There is, therefore, poor evidence on which
to base decisions for the management of psychiatric symptoms in patients with HD.
Systematic studies are required before any
definite conclusions can be drawn as to the
efficacy of various approaches. However, this
is unlikely to happen owing to the small
number of patients diagnosed with HD.
Clinicians who treat patients with HD should
be encouraged to publish reports of both
positive and negative outcomes to increase
the primary literature base in this neglected
area of care.
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