Department of Neurology

Tetrabenazine (TBZ)

Movement disorders are neurological conditions manifested either by slowness of movement, seen in Parkinson's disease, or abnormal involuntary movements, the so-called hyperkinesias (hyper: too much, kinesis: movement). The hyperkinesias are characterized by excessive, involuntary, repetitive, twisting or random jerk-like movements which may involve the face, limbs, or the entire body. One form of hyperkinesia is tardive dyskinesia, manifested typically by repetitive, chewing mouth and jaw movements. Repetitive (stereotypic) movements associated with tardive dyskinesia may also involve the trunk (rocking movements) and limbs. Tardive dyskinesia is caused by exposure to certain antipsychotics (medications used to treat hallucinations and disorders of thinking) or antiemetics (medications against nausea and vomiting). Although often transient, tardive dyskinesia may be permanent. Other examples of hyperkinesias include chorea (which means "dance" in Greek, and are brief, irregular, continuous jerky-like movements that randomly involve different muscles, as seen in conditions such as Huntington disease), athetosis (subtle twisting and writhing movements often accompanying chorea, seen for example in cerebral palsy), ballism (large amplitude, flinging movements usually of one arm or leg, most commonly following a lesion, such as a stroke, in a specific region in the brain called the subthalamic nucleus), motor and phonic tics (typically associated with Tourette syndrome, dystonia (sustained muscle contractions causing twisting and abnormal postures), myoclonus (brief muscle jerks), stereotypies (constant repetition of certain gestures and seemingly purposeful coordinated movements such as seen in chewing movements of orofacial tardive dyskinesia or body-rocking movements in children with autism), and akathisia (subjective feeling of "inner" restlessness and inability to stay still).

The neurochemical alterations underlying involuntary movement disorders are not well understood, but excess dopamine or increased sensitivity of dopamine receptors have been postulated to play a dominant role in many hyperkinetic movement disorders, particularly tardive dyskinesia, Huntington's disease and Tourette syndrome. The traditional antipsychotic or antiemetic drugs, also called neuroleptics, block dopamine receptors and are sometimes used to treat the various hyperkinetic movement disorders. However, these drugs carry the risk of tardive dyskinesia and, therefore, are not appropriate for the chronic therapy of movement disorders. Other drugs that act by reducing the dopaminergic transmission and thus ameliorate hyperkinesias include reserpine and tetrabenazine (TBZ). Both drugs cause depletion of dopamine in the brain, but reserpine also causes dopamine depletion in the peripheral nervous system and therefore, may cause low blood pressure, diarrhea and other adverse effects. The primary pharmacologic action of TBZ is depletion of dopamine in the central nervous system by inhibiting the human vesicular monoamine transporter isoform 2 (hVMAT2).

In 1979, the Food and Drug Administration granted Dr. Jankovic Investigational Exemption for a New Drug, a special permission to use TBZ in various movement disorders. Since that time Dr. Jankovic and his colleagues at Movement Disorders Clinic at Baylor College of Medicine have accumulated long-term experience with this drug in well over a thousand patients with a large variety of hyperkinesias. Data from double-blind, placebo-controlled trials conducted at Baylor and also as part of a large multicenter study (TETRA-HD) as well as longitudinal data based on observational experience at Baylor over the past quarter century was submitted to the FDA. In December 2007, an independent advisory committee concluded that TBZ is effective and safe and unanimously recommended to the FDA an approval of TBZ (Xenazine) for the treatment of chorea associated with Huntington disease, which was finally granted on Aug. 15, 2008 (http://www.fda.gov/bbs/topics/NEWS/2008/NEW01874.html). This approval was provided under the FDA's orphan products program, which is aimed at developing treatments for conditions affecting fewer than 200,000 people (Huntington disease affects 30,000 people in the USA).

Although considered safe when appropriately administered and monitored, TBZ does have potential side effects, such as drowsiness, slowness of movement (parkinsonism), mood changes (depression), and nervousness/anxiety/ restlessness (akathisia). The labeling for the TBZ (Xenazine) draws special attention to potential depression and suicidality and recommended genotyping patients (for CYP2D6) to determine if they are slow metabolizers when dosage about 50 mg per day is prescribed (see package insert for additional precautions, contraindications and other prescribing information at http://www.xenazineusa.com). The side effects of TBZ are reversible and are usually controlled by reducing the dose. Most importantly, there has been no documented TBZ-induced tardive dyskinesia, and, therefore, this dopamine depleting agent has a distinct advantage over the dopamine-blocking agents (typical neuroleptics) in the treatment of a variety of hyperkinetic movement disorders. If you have any additional questions about Xenazine, please call the Xenazine Information Center at 888-882-6013.

Selected References
(Based on studies conducted at the Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine)

Appendix

For further information about the manufacturing and distribution of TBZ (Xenazine) visit http://www.xenazineusa.com.

For additional information visit http://www.bcm.edu/neurology/pdcmdc/

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