Dopamine depleters in the treatment of hyperkinetic movement disorders

ABSTRACT

Introduction: Abnormal involuntary movements often improve in response to anti-dopaminergic drugs. In contrast to classic neuroleptics that block dopamine receptors, drugs that deplete presynaptic dopamine by blocking vesicular monoamine transporter type 2 (VMAT2) seem to be safer and have little or no risk of tardive dyskinesia. This is one reason why there has been a recent emergence of novel VMAT2 inhibitors.

Areas covered: Since the approval of tetrabenazine, the classic VMAT2 inhibitor, in the treatment of chorea associated with Huntington disease (HD), other VMAT2 inhibitors (e.g. deutetrabenazine and valbenazine) have been studied in the treatment of HD-related chorea, tardive dyskinesia and tics associated with Tourette syndrome. This review, based largely on a detailed search of PubMed, will summarize the pharmacology and clinical experience with the various VMAT2 inhibitors.

Expert commentary: Because of differences in pharmacology and pharmacokinetics these new VMAT2 inhibitors promise to be at least as effective as tetrabenazine but with a lower risk of adverse effects, such as sedation, insomnia, depression, parkinsonism, and akathisia.

KEYWORDS:

• Deutetrabenazine
• dopamine
• chorea
• Huntington disease
• hyperkinetic movements
• orphan drug
• tardive dyskinesia
• tetrabenazine
• Tourette syndrome
• valbenazine
• vesicular monoamine transporter
• VMAT2

Article highlights

• Inhibitors of presynaptic vesicular monoamine transporter type 2 (VMAT2) cause striatal dopamine depletion.

• In contrast to reserpine, which inhibits both central (VMAT2) and peripheral (VMAT1), tetrabenazine (TBZ) inhibits only VMAT2 and therefore is not usually associated with peripheral side effects such as orthostatic hypotension or gastrointestinal symptoms.

• TBZ, approved by the United States Food and Drug Administration for the treatment of chorea associated with Huntington disease, has been also found to be effective in the treatment of other hyperkinetic movement disorders, particularly tics, associated with Tourette syndrome, and stereotypies, associated with tardive dyskinesia.

• Because TBZ has to be administered at least 3 times per day and may cause a variety of side effects, such as drowsiness, depression, and parkinsonism, there is an unmet need for more effective and safer dopamine depleters with longer duration of action.

• Deautetrabenazine and valbenazine, novel VMAT2 inhibitors currently being evaluated in the treatment of various hyperkinetic movement disorders, are longer acting and seem to have fewer side effects compared to TBZ.

This box summarizes key points contained in the article.

Declaration of interest

J Jankovic has received research and/or training grants from: Huntington Study Group; Lundbeck Inc; Neurocrine Biosciences; Teva Pharmaceutical Industries Ltd. He has served as a consultant or as an advisory committee member for Teva Pharmaceutical Industries Ltd. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper is not funded