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The use of olanzapine for movement disorder in Huntington’s disease: a first case report
  1. Department of Psychiatry, Leicestershire Mental Health Service Trust, Huntington’s Disease Service, Mill Lodge, Mill Lane, Kegworth, Derby DE74 2EJ, UK. Telephone 0044 1509 670774.

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    Movement disorder is a prominent feature of Huntington’s disease and consists of involuntary and voluntary components as well as associated bradykinesia. Pharmacological treatment is problematic because of the side effects of the drugs used, which may further compromise cognitive functioning and mobility. Patients are often not subjectively aware of their movements but can be considerably disabled by them and carers are often distressed and enquire about treatment options. If drug treatment is considered it is important to achieve the maximum improvement in movements with the minimum of negative side effects. This paper describes the effect of olanzapine on movements when other treatment options had been ineffective or limited by side effects.

    Huntington’s disease is a hereditary progressive neurodegenerative disorder. It consists of a triad of symptoms comprising motor, psychological, and cognitive abnormalities. The motor component consists of involuntary choreiform movements and increasing difficulties with voluntary movement. The degree of the involuntary movements is variable but in some patients can be very marked. Progression over time of the movement disorder in Huntington’s disease can be monitored using the quantitative neurological examination (QNE). This measure has three subscales, an eye movement scale, a motor impairment scale (MIS) quantifying voluntary movement, and a chorea scale measuring involuntary movement.1 2

    Pharmacological control of the symptoms has been shown to be effective with dopamine antagonists,3 4 but their use is limited because of the side effects. Clinically the most problematic of these are sedation, cognitive slowing, increased mobility problems, and hypotension. The inability of traditional dopamine antagonists to improve functional capacity, despite ameliorating chorea, is possibly due to suppression of voluntary motor activity.4 5Tardive dyskinesia has occasionally been reported in patients with Huntington’s disease treated with these drugs.5 6 The atypical antipsychotic clozapine has been shown to be effective in improving the movement disorder. However, in a double blind randomised trial of clozapine which included patients who were already receiving traditional antipsychotic medication and a group who had not received drug treatments for their movement disorder, chorea was reduced in those who were antipsychotic naive only and the authors concluded that clozapine was of little additional benefit in Huntington’s disease.7 Olanzapine is a new atypical antipsychotic drug. It is a thienodibenzodiazepine structurally very similar to clozapine. Unlike clozapine it is not associated with the potentially serious side effect of agranulocytosis and therefore frequent blood monitoring is not necessary.

    This report describes the progress of a man who has Huntington’s disease. He developed a marked movement disorder and was unable to tolerate both sulpiride and risperidone but had symptomatic improvement when treated with olanzapine.

    He is a man in his early 50s who had a confirmatory genetic test for Huntington’s disease in 1994, after the development of clinically obvious motor symptoms. It is likely that the onset of symptoms had occurred a few years previously as he had experienced difficulties in concentration and attention at work, attributed at the time to stress, leading to the loss of employment. In addition his family, watching family videos of a few years earlier, thought that there was evidence of early signs of his movement disorder. However there was no known family history of Huntington’s disease which might have led to an earlier diagnosis. By May 1995 his involuntary movements were becoming more noticeable, although control of voluntary movement was good. A trial of sulpiride commencing at 200 mg twice daily and increasing over 1 week to 800 mg daily was undertaken with a subsequent decrease in the frequency and extent of involuntary movement recorded in case notes; unfortunately the QNE was not repeated at this time. However, the patient experienced a subjective slowing of his cognitive processes, concurrently became depressed, and decided to stop the treatment within 3 weeks. Paroxetine, a selective serotonin reuptake inhibitor antidepressant, was started at a dose of 20 mg a day, which led to an improvement in his low mood. His involuntary movements continued to cause difficulties in his daily living. He was unable to sit comfortably in a chair and when out he felt that he was disturbing others by knocking into them. He agreed to a trial of risperidone. This was started at a dose of 1mg twice daily, increasing to a dose of 1mg four times a day over a period of 2 weeks, stopped after a brief period. He developed hypotension (blood pressure 100/60 mg Hg), complaining of dizziness after the initial dose. His blood pressure remained stable, although low, after this and as there was improvement in his movements the drug was continued. However, he decided to stop the risperidone after 4 months because of his subjective experience of slowed thinking and occasional dizziness. A repeated trial of sulpiride was carried out in March 1997. Sulpiride was started at a dose of 200 mg twice a day and increased to a total daily dose of 1000 mg over 2 weeks. He was on sulpiride for 4 weeks with no improvement in his movements,so it was discontinued. The patient continued to experience low mood and after the discontinuation of sulpiride, his antidepressant drug was changed to lofepramine commencing at 70 mg once a day and increasing after a few days to 140 mg daily. There were no changes noted in his movements during this change.

    Although the patient was subjectively unaware of the extent of his movements his everyday life continued to be affected. The social venues he felt able to attend were becoming more limited and activities he wanted to pursue such as travelling abroad by air were problematic. A trial of olanzapine was then instituted. He was started on 5 mg a day in the morning. There was a marked improvement in his involuntary movements within 1 week but once again he experienced slowed thinking. However, adjusting the time of medication to the evening led to an improvement in this. Six months later the improvement in his involuntary movements is maintained. Serial quantitative neurological examination scores are illustrated in figure 1.

    Quantitative neurological examination scores showing the progress of the movement disorder. 06/95: before trial sulpiride, no medication; 05/96: before risperidone, 20 mg paroxetine daily; 07/96: 1 mg risperidone four times daily and 20 mg paroxetine daily; 03/97: before retrial sulpiride, 20 mg paroxetine daily; 04/97: 400 mg sulpiride in the mornings 600 mg at night and 20 mg paroxetine; 04/97: before olanzapine, 140 mg lofepramine daily; 06/97: 5 mg olanzapine at night, 140 mg lofepramine daily.

    In the absence of a cure for Huntington’s disease, it is very important that any interventions considered enhance the quality of life of the patient and improve overall functioning. It may not always be in the best interests of the patient to use drug treatments for the movement disorder. In those patients who have severe movements, however, a trial of treatment may be appropriate and continued if a clear benefit has been achieved. Neurological monitoring and the patient’s own perception of the effect of the drug must be taken into account.

    The mechanism by which olanzapine may have beneficial effects is unclear. Olanzapine has been shown to have high affinity for a large number of receptors including D1, D2, D4, 5HT2A, 5HT2C, 5 HT3, α-1-adrenergic, histamine H1, and 5 muscarinic receptors. This binding profile is similar to clozapine, another atypical antipsychotic drug, but substantially different to the conventional antipsychotic haloperidol.7 Preferential loss of D2 projection neurons which are involved in a feedback loop normally active in the suppression of involuntary movements is thought to be the pathophysiological basis of chorea in patients with Huntington’s disease.8 The D2 antagonist properties of olanzapine may explain its possible benefits in the improvement of chorea. However, the effect at other receptors such as D4 may also be important, as D4 receptor density has been shown to be raised in Huntington’s disease, therefore the D4/D2 ratio of activity may also be relevant. Differences in binding profile across a range of receptors may explain clinical differences in outcome when comparing different antipsychotic drugs.

    This case report indicates that olanzapine may be a useful addition to the treatments for movement disorder, for some patients, and controlled trials of its use in Huntington’s disease would be welcome.


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