The Pharmacological Therapies of Huntington’s Chorea: History
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Huntington’s Disease (HD) is an autosomal, dominantly inherited neurodegenerative disorder caused by an expansion of the CAG repeat in the huntingtin (HTT) gene. The disease generally manifests during mid-life and is clinically characterized by involuntary movements (chorea), psychiatric and behavioral symptoms, and cognitive decline. To this date, no cure or disease-modifying therapy exists. However, a wide variety of pharmacological therapies are used to improve quality of life.

  • Huntington’s Disease

1. Introduction

Huntington’s Disease (HD) is an autosomal, dominantly inherited neurodegenerative disorder caused by an expansion of the CAG repeat in the huntingtin (HTT) gene [1][2]. The disease generally manifests during mid-life and is clinically characterized by involuntary movements (chorea), psychiatric and behavioral symptoms, and cognitive decline [3][4][5]. To this date, no cure or disease-modifying therapy exists [6][7]. However, a wide variety of pharmacological and non-pharmacological therapies are used to improve quality of life [7][8][9][10][11][12].
Traditionally, dopamine-blocking agents have been used to treat chorea [13][14]. Haloperidol, developed in the mid-20th century, was one of the first treatments [15][16][17]. In the mid-1980s, tiapride became available [18][19]. Tiapride was originally developed to counteract abnormal involuntary movements in various disorders [20][21][22]. Tiapride is marketed under various brand names, such as tiapridal, tiaprida, hipokin, sereprile, and tiaprid, and is highly affordable at approximately €0.55/day for 200 mg [23][24]. As an antipsychotic and benzamide derivate, tiapride acts by selectively blocking dopamine D2- and D3-receptors [25][26]. Blocking these dopamine receptors improves the regulation of behavioral, sleep, and motor function disturbances [26][27]. Therefore, tiapride is appealing to prescribe in clinically heterogeneous movement disorders such as HD and has been widely prescribed by European HD experts over the last 40 years [28][29][30].
In March 2020, Sanofi S.A. withdraw tiapride from the Dutch market abruptly [31]. This was the only company that supplied this medicine, which was covered by health insurance, in the Netherlands [31][32]. No major safety concerns were reported, whereas many HD patients reported benefits from tiapride [28][33]. The unexpected and sudden shortage of tiapride caused much distress among patients and their caregivers, as illustrated by three representative cases below [34]. Pharmacological alternatives, which had to be introduced quickly, were not always suitable and led to disease aggravation or (severe) side effects in several patients.

2. Safety and Side-Effect Profile of Tiapride

Treatment with tiapride is generally well tolerated, particularly in HD patients (Table 1). Side effects are often rare and mild. After four decades of tiapride use in clinical practice, the most reported (in 1–10% of patients) side effects are somnolence, apathy, agitation, and during the beginning of treatment, rigidity, hypokinesia, and hypersalivation [19][24][35][36][37][38]. Less commonly (0.1–1%) reported side effects are akathisia and symptoms that are a consequence of elevated prolactin levels, such as gynecomastia, galactorrhea, and weight increase [24][36][37]. For detailed descriptions of rare side effects, we refer to the package leaflet [39]. In VigiAccess, 1897 reports of suspected potential side effects were present since tiapride became available. This is a relatively small number of reports considering that tiapride has been available for over four decades and is also used in psychiatric patients. Only those symptoms that were reported 25 times or more (arbitrarily chosen) and that are not otherwise mentioned in the patient leaflet are listed here: confusional state (n = 94), hyponatremia (n = 36), urinary retention (n = 34), loss of consciousness (n = 33), bradycardia (n = 27), thrombocytopenia (n = 26), increased serum creatine phosphokinase (n = 26), aspiration pneumonia (n = 26), and rash (n = 25). Simultaneous use of tiapride with antidepressants, benzodiazepines, analgesics, opiates, or alcohol might increase its sedative side effects [24]. Simultaneous use of tiapride with substances that might prolong QT-interval, such as class IA and III antiarrhythmic agents, domperidone, haloperidol, and pimozide, should be avoided [39].

3. Expert Opinions

Three expert surveys were included in here. Two studies focused on pharmacological chorea control [28][40]. One article summarized preferred treatment options for irritability in HD [29]. A summary of the included expert opinions can be found in Table 1. The survey with the most respondents (n = 200) was conducted among USA neurologists and describes pharmacological treatment options for HD [40]. At the time of publication, solely tetrabenazine was FDA-approved for HD chorea control. Tiapride was and is still not available in North America. However, 54% of respondents perceived tetrabenazine as having minimal or no effectiveness in suppressing HD chorea. Antipsychotics (26%) and amantadine (9.3%) were reported as off-label alternatives. The most commonly prescribed antipsychotics were risperidone (6.9%), quetiapine (6.7%), and haloperidol (5.8%). Burgunder et al. conducted a multinational survey among North American, European and Australian physicians [28]. Regional differences were visible since respondents from North America and Australia equally favored off-label antipsychotics (58%) or tetrabenazine (56%), while European respondents evidently preferred antipsychotics (87%) and specifically tiapride (50%) as initial monotherapy. Tetrabenazine was considered an alternative monotherapy by 67% of European respondents. All experts preferred antipsychotic monotherapy when comorbid behavioral symptoms were present. A combination of tetrabenazine and an antipsychotic was prescribed when symptoms were inadequately controlled by monotherapy. Efficacy and side-effect profiles were considered similar for antipsychotics and tetrabenazine, except that depression is more prevalent in the latter.
Table 1. Summary of included expert surveys.
Reference n Respondents Practice Based in HD Symptom Initial Monotherapy without Comorbidities Present Side Effects of Tiapride
Sung et al., 2018 [40] 200 100% USA Chorea Respondents preferred tetrabenazine (50%). Antipsychotics (26%) were considered off-label alternatives. NA *
Burgunder et al., 2011 [28] 52 42% EU
54% USA/Canada
4% Australia		 Chorea Worldwide respondents preferred antipsychotics (58%) as a first choice, and tetrabenazine (56%) as an alternative monotherapy. Fifty percent of EU respondents preferred tiapride. * Risperidone (43%) and olanzapine (39%) were also preferred. × Sedation,
Parkinsonism
Groves et al., 2011 [29] 55 47% EU
49% USA/Canada
4% Australia		 Irritability Respondents preferred an SSRI (57%) as first choice, and antipsychotics (31%), mirtazapine (28%), or anti-epileptic drugs (27%) as alternative monotherapy. Twenty-seven percent of EU respondents preferred tiapride. * None
reported
Legend: * Tiapride is not available in North America; × The total is more than 100% since each respondent could check more than one option.
One expert opinion focused on the pharmacological treatment of irritability [29]. Worldwide respondents preferred antipsychotics (77%) for severe aggression. In case of milder irritability symptoms, SSRIs (57%), antipsychotics (31%), and mirtazapine (28%) were endorsed. Olanzapine, risperidone, and, to a lesser extent, tiapride are specific drugs from the antipsychotic class that were favored. None of the studies reported sex differences in tiapride treatment response [28][29][40].

This entry is adapted from the peer-reviewed paper 10.3390/jpm12040589

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