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FACULTY:

Joshua J. Neumiller, PharmD, CDE, CGP, FASCP
Assistant Professor, Department of Pharmacotherapy,
College of Pharmacy, Washington State University/Elder Services
Spokane, Washington

Lindy Wood, PharmD Candidate
Department of Pharmacotherapy, 
College of Pharmacy, Washington State University

Spokane, Washington

Erin Dobbins, PharmD
Resident in Geriatrics, Department of Pharmacotherapy,
College of Pharmacy, Washington State University/Visiting Nurses Association
Spokane, Washington

Stephen M. Setter, PharmD, CDE, CGP, FASCP
Associate Professor, Department of Pharmacotherapy,
College of Pharmacy, Washington State University/Elder Services

Spokane, Washington

David R. Greeley, MD
Northwest Neurological, PLLC 
Spokane, Washington

FACULTY DISCLOSURE STATEMENTS:

Drs. Neumiller, Dobbins, Setter, and Greeley and Ms. Wood have no actual or potential conflicts of interest in relation to this program.

U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data..

 

 

First described in 1872 by the American physician George Huntington in his essay “On Chorea,” Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder.HD affects males and females in equal numbers, with an estimated prevalence of two to 10 per 100,000 people.2,3 HD is characterized by a triad of symptoms: chorea, psychiatric and behavioral changes, and cognitive decline.2-5

Although there is a juvenile variant of HD in which symptoms appear before the age of 20, the typical onset of the disease (about 90% of cases) is between 35 and 40 years.2,3 Owing to HD’s dominant hereditary nature, the children of individuals with HD have a 50% chance of developing the disorder. There is a well-documented inverse relationship between age at onset and severity of neural degeneration, with younger-onset patients experiencing a more aggressive form of the disease.2,5 The average duration of HD from onset to death is 15 years for adult-onset HD and 10 to 11 years for the juvenile-onset HD.In clinical practice, patients with HD are assessed with the Unified Huntington’s Disease Rating Scale (UHDRS), which evaluates motor function, cognitive function, behavioral abnormalities, and functional capacity.6

The first component of the triad of symptoms is motor impairment, with about 90% of patients experiencing chorea. Derived from the Latin word choreus, or “dance,” chorea describes the rapid, jerky, repetitive movements, particularly of the limbs and face, that patients experience.1,2 In the early stage of disease, the movement disorder may manifest as increased clumsiness or unsteadiness.HD can present with both positive motor symptoms (such as chorea and dystonia) and negative motor symptoms (including bradykinesia and apraxia).In later stages, bradykinesia and spasticity become more common and symptoms of chorea are less pronounced.4,5

Typical behavioral and psychiatric symptoms associated with HD include depression, agitation, mania, sexual disorders, and anxiety.As HD advances, major affective disorders and hallucinations become more common.Patients often exhibit increased suspicion and personality changes within two to five years after HD onset, and may demonstrate violent behavior or even criminal activity.3,4 Given that HD is a disabling and socially embarrassing disorder with a strong depressive component, suicide is a concern. In one study of 134 patients with HD, 8% reported suicidal ideation.8

Similar to emotional and behavioral changes, cognitive decline may be present before any motor symptoms develop.2,4 The cognitive decline that occurs in HD is progressive, with short-term memory and visuospatial functioning being affected earlier in the disease and full dementia developing as HD advances.3,4,9 Patients with HD tend to exhibit poor judgment and difficulty concentrating as they lose cognitive function.2

TREATMENT

As there is no cure for HD, therapy is geared toward symptomatic management. Hope continues to exist for a neuroprotective drug, but most therapies—including coenzyme Q10, minocycline, and creatine—have failed to offer convincing results.10 Many therapies are used for the management of the depression, behavioral disorders, and other psychiatric problems associated with HD. Treating the chorea associated with HD is a main focus of therapy. Huntington spoke of the remedies opium, belladonna, and chloral hydrate for stilling the muscles and promoting sleep.Prior to the recent approval of tetrabenazine (TBZ), no drugs were specifically approved to treat Huntington’s chorea. Many therapies have been tried, including conventional and atypical antipsychotics, benzodiazepines, dopamine depletors, dopamine agonists, gamma-aminobutyric acid agonists, and N-methyl-D-aspartate antagonists such as amantadine; most of these therapies have had mixed results, however.10 Haloperidol and fluphenazine have been used extensively to treat chorea and have been useful for psychosis and hallucinations, but these therapies are often limited by their side-effect profiles.3,10 The following section discusses TBZ and its role in the treatment of HD.

Tetrabenazine

Description and Mechanism of Action: TBZ is a benzoquinolizine derivative used for the treatment of dyskinetic disorders. Pharmacologically, TBZ is a monoamine depletor whose exact mechanism of action is unknown. Evidence suggests that TBZ may have multiple actions within the central nervous system, as illustrated in FIGURE 1. Primarily, TBZ treatment results in depletion of dopamine, serotonin, norepinephrine, and histamine from presynaptic terminals of striatal neurons.11 TBZ depletes monoamine stores by reversible inhibition of vesicular monoamine transporter 2, thus interfering with vesicular storage of monoamines within the presynaptic nerve terminal.12 TBZ also has shown weak antagonist activity at the dopamine Dreceptor in vitro, which may account for some of TBZ’s pharmacologic action.13

 

 

Pharmacokinetics: TBZ is rapidly metabolized via first-pass metabolism into two main metabolites known as alpha- and beta-dihydrotetrabenazine (DTBZ).14 Of these two compounds, alpha-DTBZ is pharmacologically active, whereas beta-DTBZ is pharmacologically inert. DTBZ is highly bioavailable and is approximately 44% to 59% protein-bound, compared with TBZ, which is approximately 85% protein-bound.14 Peak plasma concentrations of alpha-DTBZ and beta-DTBZ are achieved within one to 1.5 hours following an oral dose, and these compounds have a half-life of approximately 10 hours.14 In contrast, TBZ exhibits a half-life of about six hours. One study showed that TBZ and DTBZ follow linear kinetics between 37.5 mg and 112.5 mg/day.14 DTBZ is further metabolized by CYP2D6 to O-dealkylated DTBZ, which is subsequently excreted via the urine and feces.13

Clinical Efficacy: Two efficacy trials have been published that examined TBZ for the specific treatment of chorea associated with HD. The first study, which was not placebo-controlled, involved 19 HD patients aged 37 to 76 years (mean 56.3 +/– 12.4 years) who had an average duration of HD symptoms of 8.1 years.15 Video assessments of the motor subset of the Abnormal Involuntary Movement Scale (AIMS) were assessed by two blinded reviewers. Patients received TBZ for an average of 5.9 months, and 18 completed the study (one patient was lost to follow-up). Patients were initiated with 12.5 mg TBZ twice daily, and the dose was titrated at weekly intervals to a maximum of 50 mg three times daily. Dose titration continued until a satisfactory response was noted or until intolerable adverse events surfaced. At study end, the final mean TBZ dose was 62.5 +/– 37.4 mg/day (range 25 mg–150 mg). Fifteen patients responded favorably to the medication, two had done better prior to treatment, and one was unchanged (<.001, Wilcoxon signed rank test). Mean motor AIMS score improved from 16.2 +/– 4.8 to 12.8 +/– 4.4. Adverse events reported during the trial included akathisia, insomnia, constipation, depression, drooling, and weakness; with the exception of one case of akathisia, all reported events were mild.

The second study was a multicenter, prospective, double-blind, placebo-controlled trial involving 84 HD patients randomized to TBZ (n = 54) or placebo (n = 30).16 Exclusion criteria included presence of disabling depression, dysphagia, or dysarthria; patients who had received TBZ in the past or currently were on dopamine-altering drugs (e.g., levodopa, antipsychotics, monoamine oxidase inhibitors [MAOIs]) or memantine also were excluded. Patients were evaluated with the UHDRS total chorea score at baseline, at week 1, and then every two weeks through week 12. After week 12, patients were withdrawn from the study drug and reassessed one week later (week 13). The Clinical Global Impressions (CGI) scale was administered every two weeks, beginning at week 1. Additional assessments performed for the purpose of critically evaluating and identifying adverse effects and effects on function included the parkinsonism subscore of the UHDRS, the Barnes Akathisia Scale, the Unified Parkinson’s Disease Rating Scale Part II (which measures speech and swallowing), the Hamilton Depression Rating Scale, the Epworth Sleepiness Scale, and the Functional Impact Scale (which assesses bathing, dressing, feeding, toileting, and social isolation).

In this study, TBZ patients were initiated at 12.5 mg daily on day 1, increased to twice daily for the first week, and then titrated up by 12.5 mg/day through week 7 (maximum dose 100 mg/day divided three times daily) or until undesirable side effects were noted. For the last five weeks, patients received a consistent dose unless adverse events precluded a patient from remaining at that dose. Seventy percent of placebo patients experienced an adverse event, compared with 90.7% of the TBZ group. In the active-treatment arm, serious adverse events (SAEs) included suicide by drowning, intracerebral hemorrhage due to a fall, and, in one patient, restlessness requiring hospitalization and subsequent development of depression/suicidal ideation requiring hospitalization. Additionally, one patient reported breast cancer (the patient had a preexisting breast lump that she did not report to the research team prior to enrollment).

In this study, patients treated with TBZ had a 5.0-unit reduction in chorea severity and patients receiving placebo had a 1.5-unit reduction (adjusted mean effect size of –3.5 +/– 0.8 UHDRS units [mean +/– standard error]; 95% CI –5.2, –1.9; <.0001). TBZ-treated patients measured more favorably compared with the placebo cohort on the CGI Improvement scale (improvement of –0.7 vs. placebo patients; 95% CI –1.3, 0.2).

In summary, these clinical trials demonstrate that TBZ improves chorea symptoms in patients with HD. Patients should be closely monitored for adverse effects and tolerability, however.

 

Non–FDA-Approved Uses: TBZ has been used worldwide for the treatment of various movement disorders since the 1970s. Given the potential off-label uses of TBZ, physicians (particularly neurologists) are likely to use the drug to treat conditions other than HD. The following provides a brief discussion of other movement disorders for which the use of TBZ has been studied.

Small studies and sporadic case reports of TBZ use for the treatment of chorea exist within the literature. Chatterjee and Frucht studied the efficacy of TBZ in case reports of five pediatric patients aged 22 months to 10 years who had severe chorea secondary to encephalopathy.17 Three of these patients were reported to exhibit complete resolution of chorea symptoms, one patient experienced significant improvement, and one patient responded moderately to treatment. Additionally, two case studies of TBZ used to treat Sydenham’s chorea reported improvements in children 10 and 12 years of age.18

The treatment of spontaneous dyskinesia with TBZ has been assessed in a number of clinical studies. Effective doses of TBZ for the treatment of hyperkinetic disorders have varied considerably in reports involving adult patients.19,20 Conclusions from researchers indicate that TBZ doses should be slowly titrated based upon clinical response in patients being treated for hyperkinetic disorders.

Pakkenberg and Fog evaluated the use of TBZ for the treatment of spontaneous oral dyskinesia.21 TBZ was administered at 40 mg to 100 mg daily with or without concomitant pimozide. Both TBZ monotherapy and combination therapy with pimozide were determined to be useful for spontaneous oral dyskinesia. The combination therapy proved to be more effective than TBZ monotherapy for many patients in this study.

While TBZ can provide benefit for many drug-induced forms of dyskinesia, dopamine-depleting agents such as TBZ are not used to treat levodopa-induced dyskinesia owing to possible worsening of parkinsonian symptoms.22 Evidence indicates that neuroleptic-induced dyskinesia, unlike levodopa-induced dyskinesia, can be effectively treated with TBZ. Doses of up to 200 mg daily have resulted in resolution or improvement of dyskinetic movements in 50% or more of patients presenting with tardive dyskinesia in a number of clinical studies.11,19,20,23,24

Improvements have been noted in patients with Tourette’s syndrome treated with TBZ in uncontrolled clinical studies.19,25 One trial of 17 patients (mean age 20 years) demonstrated a marked reduction in abnormal movements in one patient, moderate improvements in four patients, and fair improvements in 11 patients. The mean duration of treatment in this study was 14 months.19

A number of studies have evaluated the efficacy of TBZ in the treatment of dystonia.19,20,26,27 A study by Jankovic and Orman did not find any benefit in patients with focal dystonias, but TBZ was noted to be an effective agent for the treatment of cranial dystonia when used in combination with lithium.19

Counseling Points for Patients 
Receiving TBZ Therapy
 

Dosing recommendations should be followed closely. Slow titration is required. The occurrence of side effects such as sedation, depression, or difficulty swallowing should be reported immediately, as they may require a dose reduction.

TBZ can impair mental or motor function and can cause sedation. You should not consume alcohol while on TBZ. Do not drive a car or operate machinery until you know how you respond to this drug.

TBZ may contribute to or exacerbate depression. Symptoms of depression (e.g., sadness, irritability, withdrawal, agitation) should be reported immediately.

TBZ may increase the risk of suicide. Suicidal ideation should be reported immediately.

Report pregnancy as soon as possible. TBZ’s effects on the fetus are unknown, and therefore the drug should be taken by pregnant women only if discussed with their physician first and only if the benefits outweigh the risks.

 

 

 

Adverse Events: The most frequently reported adverse events associated with TBZ use are related to the agent’s effects on the central nervous system, namely sedation, fatigue, insomnia, and depression.16 Akathisia and extrapyramidal effects also were noted by the Huntington Study Group in 19% and 15%, respectively, of subjects receiving TBZ.16 The majority of adverse events noted during clinical trials occurred during the upward dose-titration phases of the various studies.28 During clinical trials, subjects prematurely discontinued the study drug because of the following adverse events: mild rash, restlessness, nausea and/or dehydration, junctional rhythm (in a subject with a history of palpitations), positive fecal hemoccult test (deemed unrelated to study drug), alanine transaminase (ALT) elevation (deemed unrelated to study drug), akathisia, depression, suicidal ideation, disabling tics, abnormal coordination, unsteady gait, falls, breast cancer, suicide leading to death, increased liver-function tests, and elevated bilirubin.28

In clinical trials conducted in patients with HD, four patients receiving TBZ experienced an SAE.28 Of the four SAEs identified, two were judged to be possibly related to TBZ. One of these SAEs was a death due to suicide; the other was a fall complicated by subarachnoid hemorrhage and confusion. The two SAEs that were judged to be unrelated to TBZ were breast cancer and persistent restlessness attributed to prostatitis.

Precautions/Contraindications: The precautions associated with TBZ therapy are many. They include akathisia often manifesting as restlessness and agitation; parkinsonism; hyperprolactinemia; dysphagia; sedation and somnolence; QTc prolongation; and tardive dyskinesia. Concurrent use of dopamine agonists may increase the risk of QTc prolongation, neuroleptic malignant syndrome (NMS), and extrapyramidal disorders. In clinical trials, patients taking neuroleptics such as haloperidol, risperidone, and olanzapine were excluded; therefore, concurrent neuroleptic use is listed as a precaution. Alcohol can exacerbate sedation. Patients with comorbid hypotension should be closely monitored.13

Patients with depression or poorly treated depression should not receive TBZ. Suicidal ideation also is a contraindication. Patients taking MAOIs such as isocarboxazid, phenelzine, and tranylcypromine should not receive TBZ concomitantly. At least 20 days should elapse before TBZ replaces reserpine in a patient’s drug regimen. Because TBZ is extensively metabolized principally by CYP2D6, patients with hepatic impairment are not candidates for therapy.13

Drug Interactions: TBZ treatment has been associated with an approximate 8-msec increase in the QTc interval.13 Given this finding, the use of TBZ in combination with other agents known to prolong the QTc interval, such as levofloxacin and other agents listed in TABLE 1, should be avoided, if possible.13

Patients receiving TBZ in combination with a neuroleptic agent may be at increased risk for NMS.13 Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. NMS has been reported in association with the use of TBZ, as well as other agents that reduce dopaminergic transmission. Cases of NMS associated with TBZ therapy have been reported in the literature; therefore, practitioners and patients should be aware of this treatment risk.29-32 Additionally, the prescribing information (PI) states that concomitant use with dopamine antagonists may place patients at increased risk for extrapyramidal side effects associated with TBZ use.13

Because concomitant use of reserpine and TBZ results in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores, concomitant use is contraindicated.13 Reserpine should be discontinued for a minimum of 20 days prior to initiation of TBZ therapy. Due to the potential for decreased uptake of monoamines and inhibition of monoamine metabolism resulting in elevated catecholamine levels, concomitant use of TBZ with MAOIs is contraindicated.13

As evidenced by in vitro studies, TBZ is metabolized by carbonyl reductase to active metabolites known as alpha-DTBZ and beta-DTBZ. Reaction-phenotyping studies show that CYP3A4 and CYP2D6 enzymes are responsible for metabolizing alpha-DTBZ and that CYP2D6 is primarily responsible for metabolizing beta-DTBZ.28 Drug-interaction studies indicate that alpha-DTBZ and beta-DTBZ levels were increased—as measured by maximum concentration of drug and area under the curve—when TBZ was given following administration of paroxetine (a strong CYP2D6 inhibitor). Due to the impaired metabolism of TBZ and its metabolites when TBZ is given in combination with a strong CYP2D6 inhibitor, caution should be used when administering a strong CYP2D6 inhibitor—such as paroxetine or fluoxetine—to a patient receiving TBZ. The PI recommends halving the recommended dose of TBZ in patients taking a strong CYP2D6 inhibitor concomitantly.13

As was discussed in the section about adverse events associated with TBZ use, the agent can induce sedation and somnolence; thus, the concomitant use of TBZ with other CNS depressants may result in an increased risk of sedation. The PI specifically discourages the use of alcohol in patients receiving TBZ.13

It may be prudent to monitor for and warn patients about the potential risk of additive sedation and somnolence if TBZ is given in combination with other agents associated with CNS depression. For currently recognized drug interactions associated with TBZ.

 Potential Drug Interactions With TBZ

Potential Interaction Outcome 

Potential Offending Drugsa 

 

QTc-interval prolongation

Antiarrhythmic agents

Amiodarone, disopyramide, dofetilide, procainamide,
quinidine, sotalol

Antipsychotic agents

Chlorpromazine, haloperidol, olanzapine, paliperidone, risperidone, ziprasidone

GI agents

Cisapride

Anti-infective agents

Gatifloxacin, levofloxacin, moxifloxacin

Antineoplastic agents

Lapatinib, sunitinib

Analgesic agents

Methadone

Antianginal agents

Ranolazine

Phosphodiesterase inhibitors

Vardenafil

NMS

Antipsychotic agents

Chlorpromazine, haloperidol, olanzapine, risperidone

Extrapyramidal symptoms

Antipsychotic agents

Chlorpromazine, haloperidol, olanzapine, risperidone

Extrapyramidal symptoms

MAOIs

Isocarboxazid, phenelzine, procarbazine,
rasagiline, selegiline

Elevated catecholamine levels

Antihypertensive agents

Reserpine

Additive sedation

CNS depressants

Ethanol

 

CONCLUSION

HD is a disabling and socially embarrassing disorder that involves the cardinal symptoms of chorea, psychiatric and behavioral changes, and cognitive decline. TBZ recently received FDA approval for the treatment of chorea associated with HD. This agent provides practitioners with an additional tool within their arsenal for the treatment of this devastating disease. Given that TBZ treatment conveys clinical benefit to patients with HD as well as other movement disorders, it is of paramount importance that pharmacists understand the pharmacologic properties, potential drug interactions, and side-effect profile of TBZ to better serve those patients receiving this agent.

REFERENCES

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  2. Fahn SF, Jankovic J. Principles and Practice of Movement Disorders. Philadelphia, PA: Churchill Livingstone; 2007:369-392.
  3. Purdon SE, Mohr E, Ilivitsky V, Jones BD. Huntington’s disease: pathogenesis, diagnosis and treatment. J Psychiatr Neurosci. 1994;19:359-367.
  4. Kirkwood SC, Su JL, Conneally PM, Foroud T. Progression of symptoms in the early and middle stages of Huntington disease. Arch Neurol.2001;58:273-278.
  5. Mahant N, McCusker EA, Byth K, Graham S. Huntington’s disease: clinical correlates of disability and progression. Neurology. 2003;61:1085-1092.
  6. Huntington Study Group. Unified Huntington’s Disease Rating Scale: reliability and consistency. Mov Disord. 1996;11:136-142.
  7. Folstein SE, Folstein MF. Psychiatric features of Huntington’s disease: recent approaches and findings. Psychiatr Dev. 1983;1:193-205.
  8. Craufurd D, Thompson JC, Snowden JS. Behavioral changes in Huntington disease. Neuropsychiatry Neuropsychol Behav Neurol. 2001;14:219-226.
  9. Lawrence AD, Sahakian BJ, Hodges JR, et al. Executive and mnemonic functions in early Huntington’s disease. Brain. 1996;119:1633-1645.
  10. Bonelli RM, Wenning GK. Pharmacological management of Huntington’s disease: an evidence-based review. Curr Pharm Des. 2006;12:2701-2720.
  11. Jankovic J. Treatment of hyperkinetic movement disorders with tetrabenazine: a double-blind crossover study. Ann Neurol. 1982;11:41-47.
  12. Schreiber W, Krieg JC, Eichhorn T. Reversal of tetrabenazine induced depression by selective noradrenaline (norepinephrine) reuptake inhibition [letter]. J Neurol Neurosurg Psychiatr. 1999;67:550.
  13. Xenazine (tetrabenazine) package insert. Deerfield, IL: Ovation Pharmaceuticals, Inc; September 2008.
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  15. Ondo WG, Tintner R, Thomas M, Jankovic J. Tetrabenazine treatment for Huntington’s disease-associated chorea. Clin Neuropharmacol.2002;25:300-302.
  16. Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology. 2006;66:366-372.
  17. Chatterjee A, Frucht SJ. Tetrabenazine in the treatment of severe pediatric chorea. Mov Disord. 2003;18:703-706.
  18. Hawkes CH, Nourse CH. Tetrabenazine in Sydenham’s chorea. Br Med J. 1977;1:1391-1392.
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  20. Asher SW, Aminoff MJ. Tetrabenazine and movement disorders. Neurology. 1981;31:1051-1054.
  21. Pakkenberg H, Fog R. Spontaneous oral dyskinesia. Results of treatment with tetrabenazine, pimozide, or both. Arch Neurol. 1974;31:352-353.
  22. Rascol O, Fabre N. Dyskinesia: L-dopa-induced and tardive dyskinesia. Clin Neuropharmacol. 2001;24:313-323.
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  24. Kazamatsuri H, Chien CP, Cole JO. Long-term treatment of tardive dyskinesia with haloperidol and tetrabenazine. Am J Psychiatry. 1973;130:479-483.
  25. Sweet RD, Bruun R, Shapiro E, Shapiro AK. Presynaptic catecholamine antagonists as treatment for Tourette syndrome. Effects of alpha methyl para tyrosine and tetrabenazine. Arch Gen Psychiatry.1974;31:857-861.
  26. Lang AE, Marsden CD. Alpha methylparatyrosine and tetrabenazine in movement disorders. Clin Neuropharmacol. 1982;5:375-387.
  27. Jankovic J, Ford J. Blepharospasm and orofacial-cervical dystonia: clinical and pharmacological findings in 100 patients. Ann Neurol. 1983;13:402-411.
  28. Prestwick Pharmaceuticals, Inc. Tetrabenazine: briefing document for Peripheral and Central Nervous System Advisory Committee. December 6, 2007. www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4328b1-02-Prestwick.pdf. Accessed September 9, 2008.
  29. Petzinger GM, Bressman SB. A case of tetrabenazine-induced neuroleptic malignant syndrome after prolonged treatment. Mov Disord.1997;12:246-248.
  30. Ossemann M, Sindic CJ, Laterre C. Tetrabenazine as a cause of neuroleptic malignant syndrome. Mov Disord. 1996;11:95.
  31. Burke RE, Fahn S, Mayeux R, et al. Neuroleptic malignant syndrome caused by dopamine-depleting drugs in a patient with Huntington disease.Neurology. 1981;31:1022-1025.
  32. Mateo D, Muñoz-Blanco JL, Giménez-Roldán S. Neuroleptic malignant syndrome related to tetrabenazine introduction and haloperidol discontinuation in Huntington’s disease. Clin Neuropharmacol. 1992;15:63-68.

 

 


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