Tetrabenazine in the treatment of Huntington’s
`disease
`
`E X P E RT O P I N I O N
`
`Paleacu Diana
`Neurology Service and Memory
`Clinic, Abarbanel Mental Health
`Center, Bat-Yam, affiliated to the
`Sackler School of Medicine, Tel Aviv
`University, Tel Aviv, Israel
`
`Correspondence: Paleacu Diana
`Neurological Service and Memory Clinic,
`Abarbanel Mental Health Center, 15
`Keren Kayemet, 59110 Bat Yam, Israel
`Tel +972 3 555 2861
`Fax +972 3 555 2621
`Email paleacu@post.tau.ac.il
`
`Abstract: Tetrabenazine (TBZ), a catecholamine-depleting agent initially developed for the
`treatment of schizophrenia, when tested for other indications, has proven to be more useful for
`the treatment of a variety of hyperkinetic movement disorders. These disorders include neuro-
`logical diseases characterized by abnormal involuntary movements such as chorea associated
`with Huntington’s disease, tics in Tourette’s syndrome, dyskinesias and dystonias in tardive
`dyskinesia, also primary dystonias and myoclonus. This review will include and discuss stud-
`ies published during the period of 1960–2006 regarding the clinical effi cacy and tolerability
`of TBZ in Huntington’s disease (HD). It will also review the chemistry, pharmacokinetics and
`dynamics of the drug and its mechanism of action compared to that of reserpine, the only similar
`compound. This review emphasizes the advantage of TBZ over dopamine-depleting compounds
`used in the treatment of chorea and reveals its clinical effi cacy and side effects.
`Keywords: tetrabenazine, Huntington’s disease, chorea
`
`Introduction
`Tetrabenazine (TBZ) was initially synthesized in the 1950s by O Schneider and A
`Brossi at the research laboratory of Hoffmann-La Roche in Basel. They created TBZ
`as an antipsychotic drug as part of their research into simpler chemical compounds
`with reserpine-like activity. TBZ was studied in a number of controlled trials in
`schizophrenia patients with equivocal results (Smith 1960; Weckorciez 1960;
`Kanjilal 1962). Later clinicians came to favor the use of dopamine receptor blocking
`drugs (DRBD), like phenothiazines, for treating psychosis given the evidence of
`better effi cacy (Ashcroft 1961). However, as with many other drugs, when TBZ was
`tested for indications other than the original ones the preliminary results provided
`support for its use in disorders characterized by abnormal hyperkinetic involuntary
`movements, drug induced or primary. During the last two decades TBZ has been
`used in a multitude of movement disorders: tardive dyskinesia (Fahn 1985; Ondo
`1999; Simpson 2000; Tarsy 2000) dystonia (Manji 1998; Raja 1998; Scott 2000)
`and tremor (Storey 1997), choreic syndromes (Gimenez-Rodan 1989; Ondo 2002),
`primary dystonia (Bartels 1984; Faulstich 1985; Manji 1998; Boghen 2000; Scott
`2000), secondary dystonia (Duran 2001) and tic disorders (Vieregge 1987; Jankovic
`1988; Scahill 2000).
`
`Chemistry
`TBZ, also named Ro 1-9569 by Hoffmann-LaRoche, Inc., is a benzoquinolizine
`derivative with the following formula, 2-oxo-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7-
`hexahydrobenzo[a]quinolizine. It is a white crystalline substance with a bitter taste. The
`molecule is shown in Figure 1. It can be isolated from alkalinized biological material
`by extraction into heptane into diluted hydrochloric acid and assayed fl uorometrically
`(Quinn 1959). Chromatographic analysis of TBZ reveals peak fl uorescence at 282 nm
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`Diana
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`(Roberts MS 1981). Based on the acid-basic transition, TBZ
`is characterized by a pKa of 6.0 (Scherman 1982).
`Pharmacodynamics
`and pharmacokinetics
`TBZ is readily absorbed from the intestinal tract. After intra-
`venous administration of TBZ tagged with tritium in humans,
`54% was excreted in urine after 48 hours (Stumpf 1960).
`TBZ enters the rabbit brain rapidly after intravenous
`administration attaining maximal levels of about 34
`micrograms per gram within 10 minutes. In other tissues
`maximal concentration is seen within 15–30 minutes, latest
`in fat tissue (with concentrations in fat tissue coming last).
`The half life in various tissues (when given intravenously
`to rabbits) ranges from 0.9–2.7 hours, with the longest
`half-life being in fat tissue. After 24 hours, TBZ will have
`disappeared from most tissues, brain tissue included (Quinn
`1959). TBZ has a relatively low bioavailability, 0.049
`± 0.032 (Roberts 1986).
`TBZ is metabolized into two compounds: α- and
`β-dihydrotetrabenazine (DTBZ); α-DTBZ being the
`active compound, whereas β-DTBZ is biochemically inert.
`α- DTBZ has a high bioavailability because it is less protein-
`bound (44%–59%) compared to TBZ (83%–88%) (Roberts
`1986). α-DTBZ has higher plasma levels than TBZ and
`the half-life is longer, 10 hours versus 6 hours (in humans)
`(Roberts 1986). Therefore it has to be administered two to
`three times a day.
`Acute toxicity in mice LD 50 is found to be 150 mg/kg
`by intravenous injection, 400 mg/kg by subcutaneous
`injection and about 550 mg/kg by oral administration,
`being about ten times less toxic than reserpine, another
`cathecolamine depletor). Toxic doses produce spasms with
`respiratory inhibition and opisthotonus. Chronic toxicity
`observed in rats given a daily dose of 8–15 mg/kg daily
`
`in their food for 13 weeks was well tolerated and growth
`was little infl uenced and neither blood nor organ exami-
`nations showed any abnormality (Lingierde 1963). TBZ
`crosses the placenta but no case of teratogenicity has been
`reported in humans. It is also excreted in breast milk and
`therefore breastfeeding should be avoided while taking
`TBZ (Roberts 1986).
`
`Mechanism of action
`The mechanism of action of TBZ is well known (Pettibone
`et al 1984). It acts mainly as a reversible high affi nity inhibitor
`of monoamine uptake into granular vesicles of presynaptic
`neurons and secondary depletion at low doses, as well as a
`weak D2 postsynaptic receptor blocker in high doses (Reches
`1983) TBZ depletes all three monoamines, but particularly
`dopamine (Pletscher et al 1962). One in vivo study of rats
`showed that TBZ decreased dopamine levels by 40%, sero-
`tonin by 44%, and norepinephrine by 41% in the brain (Lane
`et al 1976).
`The effect of a seven-day repetitive administration of
`TBZ in rats was investigated by examining the locomotive
`behavior and histomorphological fi ndings of substantia nigra
`in rats. These studies compared the effect of a single dose of
`TBZ which caused decrease of voluntary movements and no
`histological changes versus repetitive administration of TBZ
`which demonstrated irreversible and signifi cant changes
`in spontaneous locomotion as well as histological changes
`in the neurons of the substantia nigra pars compacta. The
`results suggest that this could be a new and useful model
`for the behavioral characteristics and anatomical pathol-
`ogy of Parkinson’s disease as one of the oxidative stress
`models induced by abnormal dopamine metabolism (Satou
`et al 2001).
`In an autopsy study of Huntington’s disease (HD)
`patients, those patients who had received TBZ displayed a
`
`CH3O
`
`CH3O
`
`N
`
`CH2CH(CH3)2
`
`O
`Figure 1 Tetrabenazine, a benzoquinolizine derivative with the chemical name, 2-oxo-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydrobenzo[a]quinolizine.
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`greater overall depletion of monoamines than patients not
`exposed to TBZ, primarily in the caudate, but also, to a lesser
`degree, in the amygdala, hippocampus, and temporal lobe
`(Pearson and Reynolds 1988). PET studies w/11-C-raclopride
`show a 28% reduction in striatal binding after TBZ.
`α- DTBZ has been shown to inhibit monoamine uptake
`driven by a transmembrane proton elecrochemical gradi-
`ent generated by an ATP-ase proton pump using a special
`transporter (VMAT). In rat fi broblasts the central neural
`transporter VMAT2 is inhibited by TBZ, but the periph-
`eral endocrine specifi c VMAT1 is not (Masuo et al 1990;
`Erickson et al 1996). VMAT2 is a large protein with 12
`transmembrane helices encoded by the VMAT2 gene
`localized to chromosome 10q25. VMAT2 is expressed
`primarily in the brain. VMAT1 is encoded by a gene on
`chromosome 8p21.3 and is expressed in the periphery
`(Gonzalez et al 1994).
`The dual effects of TBZ are thought to be responsible both
`for its therapeutic effects as well as its side effects.
`Tetrabenazine versus reserpine
`The pharmacologic agent most similar to TBZ is reserpine
`(R). Both TBZ and R seem to reduce cells’ capacity to store
`monoamines, therefore causing a depletion of the brain stor-
`age of these amines and in the case of Reserpine a depletion
`of the amines in the peripheral sites. Both drugs act centrally
`on VMAT2, but reserpine also inhibits VMAT1 peripher-
`ally, which may explain the higher frequency of hypotension
`and gastrointestinal side effects it causes. While reserpine
`binds irreversibly to both VMAT’s, TBZ binds reversibly
`only to VMAT2. TBZ displays a much shorter half life than
`reserpine (hours as opposed to days) and has a more rapid
`onset of action. This confers an advantage on TBZ in the
`clinical setting as its effi cacy can be assessed more rapidly
`and its side effects abate more rapidly upon discontinuation
`of drug usage. Differences summarized in Table 1.
`
`Table 1 Difference between tetrabenazine and reserpine
`
`Tetrabenazine
`Reserpine
`Monoamine
`Central through
`Central and peripheral
`depletion
`VMAT2
`through VMAT1 and
`
`
`VMAT2
`Binding
`Reversible
`Non-reversible
`Post-synaptic
`YES
`NO
`effects
`(weak D2 blocker
`
`at high dose)
`T1/2
`10 hrs
`Side effects
`NO
`
`
`
`
`
`Several days
`YES
`(gastrointestinal and
`hypotension)
`
`Tetrabenazine in Huntington’s disease
`
`Huntington’s disease
`HD is a genetic neurological disease, which manifests a triad
`of psychiatric, cognitive and movement disorders. HD is
`inherited in an autosomal dominant fashion with complete
`penetrance. The prevalence rate in the United States has been
`estimated at 5–10 per 100,000 (Jancovic et al 1995). Genetic
`studies of families with a very high prevalence and incidence
`of HD from the Lake Maracaibo area in Venezuela led to the
`discovery of an unstable trinucleotide (CAG) repeat present
`in the gene on chromosome 4. The number of CAG repeats in
`normal subjects is up to 29 repeats, while the presence of 36
`or more CAG repeats ensures the development of HD (The
`Huntington’s Disease Collaborative Research Group 1993).
`The phenomena of anticipation and paternal imprinting have
`been well described in HD. The disease often presents with
`psychiatric problems or one type of hyperkinetic move-
`ment disorder, usually chorea. HD patients slowly progress
`over 15–20 years to a bedridden state. In advanced stages
`functional disability develops with dysphagia, dysarthria,
`prominent chorea with motor impersistence and in advanced
`stages a hypokinetic rigid state accompanied by dementia,
`depression and psychosis. HD represents the neurological
`disease with the highest rates of depression and suicide.
`Unfortunately there is no treatment that can cure or slow
`the course of the disease. Only modest symptomatic treatment
`options exist for those suffering from HD, mostly focused
`on ameliorating depression, psychosis, and chorea. Many
`therapeutical modalities, most of them including dopamine
`receptor blockers or dopamine depletors have been evalu-
`ated over the years, most of them in open label studies or
`presented as case reports. Few randomized double-blind
`studies with TBZ have been done in HD. (Mc Lellan et al
`1974; Sajatovic et al 1991; Van Vugt et al 1997; Huntington
`Study Group 2006).
`Huntington’s disease
`and tetrabenazine treatment
`One of the main reasons for using TBZ instead of dopamine
`receptor blockers is its relative safety, exemplifi ed by the
`fact that TBZ has never been documented as having caused
`tardive dyskinesia (TD). This is a major advantage of TBZ
`over the typical neuroleptics, since between 25%–40% of
`those chronically treated with DRBD eventually develop
`TD (Smith and Baldessarini 1980).
`The fi rst reports of the therapeutic potential of TBZ in
`patients with HD were published in the 1960’s (Brandrup
`1960; Sattes 1960; Sattes and Hase 1964). Since the
`1970’s, numerous other clinical trials with relatively
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`small numbers of patients have demonstrated the ben-
`efi cial effects of TBZ for patients with chorea (Fog and
`Pakkenberg 1970; Gilligan et al 1972; Swash et al 1972;
`Huang 1976; Toglia et al 1978; Kingston 1979; Asher and
`Aminoff 1979; Jancovic 1982, 1983; Jancovic and Orman
`1988; Gimenez-Roldan and Mateo 1989; Jancovic and
`Beach 1997; Ondo et al 2002; Paleacu et al 2004; Kenney
`and Jancovic 2006).
`TBZ was approved for the treatment of chorea in the
`United Kingdom in 1971. It is also available in Canada and
`Australia, as well as in several European countries. TBZ
`is still unavailable in the United States, though it has been
`obtained by selected physicians via the Notice of Claimed
`Investigational Exemption for a New Drug (IND). However,
`in spite of its low availability, several long-term studies
`of TBZ in movement disorders, including HD, have been
`reported from the US.
`There have been fi ve major studies, which assessed the
`long-term effi cacy of TBZ in chorea patients, most of them
`with HD. The most recent, a phase-III study assessing the
`safety, effi cacy, and dose-tolerability of TBZ for amelio-
`rating chorea in 84 patients with HD, was published by
`the Huntington Study Group (HSG) in 2006. HD patients
`were randomized to placebo (n = 30) or TBZ (n = 54) up to
`100 mg/day at a titration rate of 12.5 mg per week. Based
`on the chorea score of the Unifi ed Huntington Disease
`Rating Scale (UHDRS), TBZ signifi cantly reduced the
`chorea score by 5.0 points compared to 1.5 for placebo
`(p < 0.0001). Likewise, the CGIC showed signifi cantly
`higher improvement rates in patients treated with TBZ
`in comparison to those given placebo. There were fi ve
`withdrawals in the TBZ treatment group and fi ve serious
`adverse events (SAE) including one suicide, which was felt
`to be due to situational depression rather than TBZ-induced
`depression. There were no SAE in the placebo group.
`A retrospective chart analysis of 76 hyperkinetic patients
`in a pediatric population treated at Baylor College of Medi-
`cine from 1996–2004 revealed signifi cant improvement in
`chorea in 89% of the patients (Vuong et al 2004).
`In a study comprising 118 patients with hyperkinetic
`movement disorders (28 diagnosed with HD), patients
`were assessed by phone interview using the Clinical Global
`Impression of Change (CGIC) and the overall effi cacy of
`treatment was shown via a composite score made up of the
`patient’s score and the caregiver’s score. Signifi cant improve-
`ment of hyperkinesias was seen in 61% of patients, with
`a subgroup of subjects with chorea and facial dyskinesias
`responding most favorably (Paleacu et al 2004).
`
`In another small study of 19 HD patients treated with
`TBZ, the follow-up was carried out in a prospective fashion.
`The evaluation was done using the Abnormal Involuntary
`Movement Scale (AIMS), which was done by two separate
`investigators blinded to the drug administered. Eighteen
`patients completed and these patients were rated at 3.3
`months at a fi nal mean dose of 62.5 ± 37.4 mg/day. Fifteen
`patients scored better than before treatment, the scores of one
`remained the same and the scores of two others worsened
`(Ondo et al 2002).
`The fi rst published study assessing the long-term effi cacy
`of TBZ in 400 hyperkinetic movement disorders patients
`selected from a large group of 526 included 29 HD patients.
`These patients improved by 82.8% on a scale of 1 to 5 (where
`1 = improvement, 4 = no response and 5 = worsening). The
`average treatment duration was 28 ± 31.1 months (Jancovic
`and Beach 1997).
`Kingston summarized the experience of 40 patients
`who had been receiving TBZ for almost 7 years for sev-
`eral movement disorders including chorea. 75% of these
`patients experienced marked or moderate improvement
`(Kingstone 1979).
`A single-blind crossover study with a pretreatment phase,
`active drug, followed by placebo in 26 patients with HD,
`TD, and dystonia found that 54% experienced marked or
`moderate improvement of chorea with TBZ for the 3-week
`duration of the study (Asher and Aminoff 1979). Many
`studies that included a mixed group of movement disorders
`mention that the patients with chorea and TD responded
`better than patients with dystonia or tics.
`A double-blind prospective crossover study of 20 patients
`assessed TBZ versus placebo for its effect on a variety of
`hyperkinetic movement disorders (Jancovic 1982). TBZ was
`found to improve the hyperkinesia score more than placebo
`to a statistically signifi cant degree. Patients noted func-
`tional improvement, but this endpoint was not assessed in a
`quantitative manner. An open-label follow up of these same
`patients found that 62% of patients initially enrolled in the
`double-blind crossover study continued to display moderate
`improvement of the movement disorder 6–18 months later
`(Jancovic 1983). Major studies reporting on TBZ effi cacy
`on chorea are summarized in Table 2.
`
`Dosing issues
`TBZ is usually initiated at a dose of 12.5 mg twice a day
`and is slowly titrated in two or three divided doses up to
`150–200 mg/day in increments of 25 mg/week. In studies
`and in daily practice, given the short half-life, dosing TID is
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`Tetrabenazine in Huntington’s disease
`
`5 point reduction in HD
`compared to1.5 in placebo
`patients
`(p < 0.0001)
`89% of the patients improved
`
`Table 2 Major studies in which chorea, including HD, patients were treated with TBZ showing treatment outcome
`Authors and year
`Number of
`Outcome measures
`Outcome
`of publication
`patients
`
`Huntington study
`84 HD patients
`Reduction in chorea
`group 2006
`
`score of the UHDRS
`
`
`
`
`
`
`Vuong et al 2004
`76 pediatric
`Chorea improvement by
`
`patients
`CGIC
`Paleacu et al 2004
`118 patients with
`CGIC
`
`hyperkinetic
`
`
`movement
`
`
`disorders, 28 HD
`
`Ondo et al 2002
`19 HD patients
`AIMS
`
`
`
`Jancovic and
`400 hyperkinetic
`Modifi ed CGIC
`Beach 1997
`patients, 29 HD
`(from 1–5)
`
`
`
`Jancovic 1982
`20 hyperkinetic
`Functional
`
`patients
`
`Asher and
`26 patients with
`Clinical
`Aminoff 1979
`chorea, TD, tics
`
`Kingstone 1979
`40 hyperkinetic
`Clinical
`
`patients
`
`
`61% of patients improved
`(chorea improved in19/28
`patients)
`
`79% of patients improved
`(15/19)
`Overall improved by 82.8%
`97% of chorea patients
`improved (28/29 )
`62% of patients improved
`
`54% of chorea patients
`improved
`75% marked to moderate
`improvement
`
`Abbreviation: UHDRS, unifi ed Huntington disease rating scale; CGIC, clinical global impression of change; AIMS, abnormal involuntary movement scale
`
`sometimes necessary. The dose escalation is stopped when
`the patient experiences a clear therapeutic effect or intoler-
`able side effects. This technique might indeed create a bias
`towards an increase in side effects in many clinical studies on
`TBZ as most studies are designed to increase the dose until
`intolerable side effects are noted and then the dose is slightly
`decreased to alleviate the side effects. Most drug-related side
`effects can be alleviated by lowering the dose. Overdose in
`a case of self-poisoning with tetrabenazine was described
`in a 27-year-old female without any signifi cant sequelae,
`except for sedation, after taking approximately 1 gram of
`TBZ (Kidd et al 1972).
`
`Tolerability and side effects
`The most common immediate side effects include drowsi-
`ness/sedation, weakness, parkinsonism, depression and
`acute akathisia, all of which are reversible with decreased
`dosing (Jancovic 1997; Paleacu 2004). Several studies have
`observed that younger patients tolerate TBZ better than the
`elderly. It is also notable that side effects vary slightly across
`different age groups: while younger patients showed a trend
`to experience more insomnia and depression, older patients
`seemed more likely to develop parkinsonism (Hunter 2002;
`Paleacu 2004). Other rare side effects include: insomnia,
`nervousness/anxiety, nausea and vomiting, tremor, memory
`
`problems, confusion, “trance-like/zombie”, orthostatic hypo-
`tension, balance and gait diffi culties, dizziness, diarrhea,
`headaches, hallucinations, paresthesias, pharyngeal spasm
`and pain, blurred vision, panic attacks, paranoia (Jancovic
`and Beach 1997).
`Changes in clinico-chemical tests during 12 months
`on TBZ were always minor, nearly always unsystematic
`and, on the whole, tended more towards a normalization of
`values. Even taking into account the limitations inherent in
`an uncontrolled trial, the conclusion was reached that long-
`term treatment with TBZ seems to be quite safe (Jancovic
`and Beach 1997). The extrapyramidal side effects of TBZ
`include parkinsonism, acute dystonia and akathisia and rarely
`neuroleptic malignant syndrome (NMS). It is particularly
`notable than not one single case of tardive dyskinesia has
`been reported with TBZ; it is this fact which confers its great
`advantage over dopamine receptor blockers. Concurrent use
`of antipsychotics with tetrabenazine can induce parkinsonism
`in HD patients (Moss and Stewart 1986) or acute dystonic
`reactions (Schott et al 1989). In one of the NMS cases,
`factors potentiating NMS included a high dosage of tetra-
`benazine exceeding the accepted therapeutic range together
`with co-medication with the dopamine-synthesis inhibitor
`alpha-methylparatyrosine, while in an other case, abrupt
`introduction of the drug and discontinuation of concomitant
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`neuroleptics may have contributed to this adverse reaction.
`Uneventful recovery occurred in both cases without the need
`for drugs specifi cally enhancing dopaminergic transmission,
`while rechallenge by tetrabenazine with conventional doses
`and slow upward titration was not followed by recurrence of
`the NMS (Burke et al 1981; Mateo et al 1992; Osseman et
`al 1996). Other serious adverse events included pneumonia
`(Shoulson 1981) severe dysphagia (Jancovic and Beach
`1997), and suicide (Gimenez-Roldan 1989). While it is well
`known that depression is extremely prevalent in HD and that
`suicide rates for this population are among the highest of
`those for all neurological diseases, TBZ, while capable of
`potentiating depression, did not seem to be directly involved
`in the suicide cases or in any other fatalities which occurred
`during treatment.
`
`Conclusion
`TBZ, a dopamine-depleting drug with a unique pharmaco-
`logic mechanism, has been found to be safe and effi cacious
`for the treatment of a variety of hyperkinetic movement
`disorders, including HD. In the absence of modern disease
`modifying treatments for HD, symptomatic drug treatments
`such as TBZ remain important. These drugs, ideally, should
`be effi cacious and devoid of debilitating side-effects.
`Though most published studies are not double-blind,
`placebo-controlled trials, the sustained long-term benefi t of
`patients speaks in favor of TBZ’s clinical effi cacy in HD.
`Furthermore, TBZ does not cause TD, which is its major
`advantage over dopamine receptor blockers. It also has gener-
`ally well tolerated side effects that are usually dose-related
`and therefore resolvable by decreasing doses or employing
`slow titration. Potentially fatal side effects such as dysphagia
`and depression are rare, though their existence mandates
`close monitoring of patients.
`Based on his observations and previous open studies
`demonstrating TBZ efficacy in chorea Mc Lellan may
`have rightfully affi rmed that “tetrabenazine is the drug of
`fi rst choice for the suppression of chorea in patients with
`Huntington’s disease” (McLellan 1974).
`
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