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For personal use only. Not to be reproduced without permission of the editor ([email protected]) 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 www.pjonline.com 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. References 1. Jankovic J. Huntington’s disease. Available at www.bcm.edu/neurology/struct/parkinson/huntington.html (accessed 13 November 2006). 2. Ho LW, Carmichael J, Swartz J, Wyttenbach A, Rankin J, Rubinsztein DC. The molecular biology of Huntington’s disease. Psychological Medicine 2001;31:3–14. 3. Bonelli RM, Wenning GK, Kapfhammer HP. Huntington’s disease: present treatments and future therapeutic modalities. International Clinical Psychopharmacology 2004;19:51–62 4. Rosenblatt A, Leroi I. Neuropsychiatry of Huntington’s disease and other basal ganglia disorders. Psychosomatics 2000;41:24–30. 5. Squitieri F, Cannella M, Porcellini A, Brusa L, Simonelli M, Ruggieri S. Short-term effects of olanzapine in Huntington’s disease. Neuropsychiatry, Neuropsychology and Behavioral Neurology 2001;14:69–72. 6. Paleacu D, Anca M, Giladi N. Olanzapine in Huntington’s disease. Acta Neurologica Scandinavica 2002;105:441. 7. Bonelli RM, Niederwieser G, Tribl GG, Koltringer P. High-dose olanzapine in Huntington’s disease. International Clinical Psychopharmacology 2002;17:91–3. 8. Dallocchio C, Buffa C, Tinelli C, Mazzarello P. Effectiveness of risperidone in Huntington’s chorea patients. Journal of Clinical Psychopharmacology 1999;19:101–3. 9. Bonelli RM, Niederwieser G. Quetiapine in Huntington’s disease: a first case report. Journal of Neurology 2002;249:1114–5. 10. Erdemoglu AK, Boratav C. Risperidone in chorea and psychosis of Huntington’s disease. European Journal of Neurology 2002;9:177–85. 11. Mclellan DL, Chalmers RJ, Johnson RH. A double-blind trial of tetrabenazine, thiopropazate and placebo in patients with chorea. Lancet 1974;26:104–7. 12. Jankovic J. Treatment of hyperkinetic movement disorders with tetrabenazine: a double-blind crossover study. Annals of Neurology 1982;11:41–7. 13. Mateo D, Munoz-Blanco JL, Gimenez-Roldan S. Neuroleptic malignant syndrome related to tetrabenazine introduction and haloperidol discontinuation in Huntington’s disease. Clinical Neuropharmacology 1992;15:63–8. 14. Snaith RP, Warren H. Treatment of Huntington’s chorea with tetrabenazine. Lancet 1974;1:413–4. 15. De Tommaso M, Di Fruscolo O, Sciruicchio V, Specchio N, Cormio C, De Caro MF et al. Efficacy of levetiracetam in Huntington’s disease. Clinical Neuropharmacology 2005;28:280–4. 16. Petrikis P, Andreou C, Piachas A, Bozikas VP, Karavatos A. Treatment of Huntington’s disease with galantamine. International Clinical Psychopharmacology 2003;19:49–50. 17. Seitz D, Millson R. Quetiapine in the management of psychosis secondary to Huntington’s disease: a case report. Canadian Journal of Psychiatry 2004;49:413. 18. Meco G, Bonifati V, Alessandri A, Brusa L. Risperidone in Huntington’s disease. Human Psychopharmacology 1995;10:353–4. 19. Madhusoodanan S, Brenner R. Use of risperidone in psychosis associated with Huntington’s disease. American Journal of Geriatric Psychiatry 1998;6:347–9. 20. Saft C. Andrich J, Kraus P, Przuntek H. Amisulpride in Huntington’s disease. Psychiatrische Praxis 2005;32:363–6. 21. Paulsen JS, Nehl C,Hoth KF, Kanz JE, Benjamin M, Conybeare R et al. Depression and stages of Huntington’s disease. Journal of Neuropsychiatry and Clinical Neurosciences 2005;17:496–502. 22. Schoenfield M, Myers RH, Cupples LA, Berkman B, Sax DS, Clark E. Increased rate of suicide among patients with Huntington’s disease. Journal of Neurology, Neurosurgery and Psychiatry 1984;47:1283–7. 23. Bonelli RM. Mirtazepine in suicidal Huntington’s disease. Annals of Pharmacotherapy 2003;37:452. 24. De Marchi N, Daniele F, Ragone MA. Fluoxetine in the treatment of Huntington’s disease. Psychopharmacology 2001;153:264–6. 25. Rosenblatt A, Ranon NG, Nance MA, Paulsen JS. A physician’s guide to the management of Huntington disease. Available at www.hsc-ca.org/english/pdf/Physicians _Guide.pdf (accessed 14 November 2006). www.pjonline.com