Is there a cure for late dyskinesia

TETRABENAZINE (NITOMAN) IN M. HUNTINGTON AND LATE DYSKINESIA

The benzoquinolizine derivative Tetrabenazine (NITOMAN) was developed as a neuroleptic back in the 1950s. It failed to hold its own as an antipsychotic, but has been used for decades in the UK, for example, for hyperkinetic movement disorders.1,2 Difficult dose finding and strongly dose-dependent interfering effects such as extrapyramidal motor symptoms and depression with suicide attempts have apparently limited the applicability of tetrabenazine.1-5

Tetrabenazine has been on the market in Germany since March 2007 for the symptomatic treatment of Huntington's disease and for at least moderate tardive dyskinesia when other measures have failed.

A causal therapy of the Huntington's disease does not exist. Whether symptomatic treatment of the hyperkinesia is necessary must be carefully considered in each case. Choreatiform symptoms are initially in the foreground and are important for the diagnosis, but represent only part of the movement disorders and recede in the course of the disease compared to other symptoms such as dystonia or rigidity. Functionally restricting are mainly gross motor problems such as gait disorders. The traditional term Huntington's disease is therefore rather avoided today. Depression is common, and around one in four people who suffer from it makes a suicide attempt.6 Neuroleptics such as haloperidol (HALDOL, etc.) or tiapride (TIAPRIDEX, etc.) have so far been used for chorea in need of treatment. However, their benefits are poorly documented. Repeated attempts to stop the patient should be used to check whether the symptoms of chorea are still present and whether their therapy is still required.7

With neuroleptics-related Tardive dyskinesia According to meta-analyzes, there is no evidence of benefit and safety both for the frequently recommended dose reduction and for masking by higher doses.8 Also the effectiveness of a variety of drug treatment attempts including tiapride9 is not proven according to evaluations by the Cochrane Collaboration.10

PROPERTIES: Tetrabenazine inhibits the uptake of dopamine and noradrenaline, but also of serotonin, into the storage vesicles of the presynaptic neurons.11 In addition to the reversible transmitter depletion effect, tetrabenazine has weak post-synaptic antagonistic properties on the dopamine receptor.12,13
The maximum daily dose is 200 mg. Due to the low and variable bioavailability14 (5% ± 3%), however, the required dosages are difficult to calculate. In Huntington's disease, 25 mg three times a day are initially provided.11 However, 12.5 mg / day can also be sufficient.1 This corresponds to the recommended daily starting dose for tardive dyskinesia.11

EFFECTIVENESS AT CHOREA HUNTINGTON: In a twelve-week, placebo-controlled, double-blind study with 84 outpatients, the influence of a maximum of 100 mg tetrabenazine daily on seven aspects of chorea symptoms (UHDRS *) is examined. The actually relevant overall motor skills, the overall clinical impression, roughly assessed according to CGI **, and everyday skills (UHDRS) are recorded secondarily.15 Included are on average almost 50-year-old patients whose chorea symptoms averaged 15 out of 28 possible points, whose overall motor skills are impaired with around 46 out of 124 points and who have neither swallowing nor speech disorders nor impairing depression. However, the majority (60%) take antidepressants, 17% take benzodiazepines.

*

UHDRS = Unified Huntington's Disease Rating Scale. This records motor, cognitive, functional and behavioral symptoms. 31 motor aspects are rated with 0 to 4 points each, i.e. a maximum of 124 points, of which 7 aspects relating to chorea are rated with a maximum of 28 points. Find it at http://huntingtondisease.tripod.com

With placebo, the chorea symptoms recorded after nine and twelve weeks decreased by an average of 1.5 points, with verum by 5 points (p <0.0001). However, the overall motor skills are no different. The overall clinical condition changes statistically significantly, but only slightly: in placebo users it hardly differs from the initial value with an average of 3.7 points (unchanged = 4 points **), in verum users it is "minimally" improved with 3 points . Another argument against clinical relevance is that everyday skills are better under placebo than under tetrabenazine.15

**

CGI = Clinical Global Impression for recording the overall clinical impression; Improvement is rated on a 7-point scale; 4 points = unchanged, 1 point = maximally improved, 7 points = maximally deteriorated.

A second five-day phase III study with 30 participants, which is only published as an abstract, turns out negative: The chorea symptoms (UHDRS) worsen in those who responded to the drug before the start of the study and then discontinued it, compared to the continued ones Ingestion not (p = 0.0773).16

Other small mostly older studies on tetrabenazine in patients with Huntington's disease1,12,17,18 or different movement disorders2,19-22 do not meet today's requirements and do not allow any conclusions to be drawn.

Evidence of loss of effectiveness in some of the patients can be found in early psychiatric studies, but also in the treatment of movement disorders.2-4 In the USA, the data to date have apparently not been sufficient for approval in Huntington's disease.23 The company itself anticipated difficulties in advance due to the negative second phase III study.24

EFFECTIVENESS IN LATE DYSKINESIA: The data are inadequate: two old, small, randomized one-center studies with 4 and 19 patients with tardive dyskinesia and a small cross-over study that also included 10 patients with tardive dyskinesia do not meet today's standards.21,22,25 In addition, we mainly find retrospective evaluations of patients with various movement disorders.13,19,26

INTERFERENCES: The focus is on sleepiness / somnolence (32% versus 3% with placebo) and fatigue (22% versus 13%). On the other hand, insomnia also increased (26% vs. 0%). Motor-wise, frequent hyperkinesia (9% vs. 0%), ataxia (9% vs. 0%) and falls (17% vs. 13%) are evident. Serious psychiatric disturbances such as depression (15% vs. 0%), anxiety (15% vs. 3%) and agitation (15% vs. 0%) are to be expected,15 which - like suicidality - are also described in early psychiatric studies.2,3,5

According to data from 400 patients with an average of 42 years of age with various movement disorders who take tetrabenazine on average for a little longer than two years, Parkinsonoid in 29% of patients, akathisia in 10%, acute dystonic reactions and tremors in 3% and dysphagia in 0 , 5% observed. 55% discontinue therapy, 23% because of interfering effects. 5% of these still young patients die. However, as in the case of deaths in other studies, the authors see20,26 unrelated to the medication.13 British doctors report severe dysphagia and pneumonia resulting in death in three out of five people treated, including one with confirmed aspiration pneumonia.27 Significant weight gain and blood sugar were already noticed in early psychiatric studies.3,4

The malignant neuroleptic syndrome and severe hyperthermia, which are dreaded as disruptive neuroleptic effects, also occur.28-30 Since acute extrapyramidal motor symptoms, as occurs with tetrabenazine, are considered a risk factor for tardive dyskinesia,31 this late damage cannot be ruled out even after taking tetrabenazine.

COSTS: Based on a daily dose of 75 mg tetrabenazide (NITOMAN), the treatment is 164 (three times as expensive per month as with a generic tiapride (TIAPRID-CT, 52 € / month for 3 x 100 mg / day) and about 20 times as expensive as a haloperidol generic (e.g. HALOPERIDOL HEXAL, € 8 per month at 2 x 2 mg / day).

The neuroleptic has been more than 50 years old since March 2007 Tetrabenazine (NITOMAN) for the symptomatic therapy of hyperkinesia in Huntington's disease and after unsuccessful therapeutic measures for at least moderate tardive dyskinesia in Germany.

There is insufficient data for patients with Huntington's disease: only one of two phase III studies was positive for the primary endpoint, chorea symptoms, but not for total motor skills. Placebo users do even better for everyday functions. Ataxia, extrapyramidal motor symptoms, and frequent falls while taking tetrabenazine may explain this.

We do not understand the approval for tardive dyskinesia on the basis of old miniature studies and retrospective evaluations.

Depression is common. There have been deaths as a result of suicide or dysphagia as well as unexplained genesis.

We do not recommend the use of tetrabenazine.