Arches. Photo by Daniel Chia
Jun
26
2010

Tetrabenazine

Tetrabenazine

Chorea is one of the most common and debilitating motor symptoms experienced by people with Huntington’s Disease. Tetrabenazine (TBZ) has been the drug of choice for treating chorea in 10 countries for more than a decade. However, TBZ has not been widely used in the U.S. because, until recently, the drug had not been approved by the FDA for the treatment of chorea. In August of 2008, the FDA approved a form of TBZ, called Xenazine, for the treatment of chorea, making the drug available to HD patients in the U.S. TBZ is also available under the name Xenazine in Europe and Australia, and under the name Nitoman in Canada. According to reports from countries where TBZ has been used for a longer period of time, 80% of patients show an improvement in chorea. It is important to note that TBZ treats some of the symptoms of HD but is not a cure because it does not affect the underlying mechanisms or progression of the disease.

How does TBZ work?^

Effects of Dimebon

TBZ cannot fix the proteins that are damaged in HD, but it can help reduce one of their harmful effects: chorea. Recall that chorea is believed to be caused by increased activity of the neurotransmitter dopamine. TBZ exerts its anti-choreic effects by reducing the amount of dopamine in the brain in two ways. The first way and more widely recognized way is by preventing dopamine from being released into pockets at the end of each neuron called vesicles. These pockets store neurotransmitters, like dopamine, and release them into the synapse at certain times. When a signal to release the neurotransmitters is received, the vesicles are transported to the ends of nerve cells for release through the membraneof the neuron into the synapse. Special proteins called vesicular monoamine transporters (VMATs) are responsible for putting neurotransmitters into the vesicles. TBZ binds to the VMATs, preventing them from performing this function. As such, neurotransmitters like dopamine are not stored in vesicles and cannot be released into the synapse where they would otherwise affect other nerve cells.

The second way that TBZ reduces dopamine is by blocking dopamine receptors. TBZ binds to receptors on the surface of the receiving nerve cell, blocking dopamine from binding and passing on its message. The mechanism of inhibiting dopamine receptors, however, is thought to be less significant at the TBZ dosages used in HD patients. For more information on the neurobiology of HD, click here. Because it has the potential to block dopamine on both sides of the synapse, TBZ is thought to be that much more effective at treating choreic movement disorders.

What are the possible side effects of TBZ?^

TBZ depletes neurotransmitters other than dopamine in the brain, such as serotonin and norepinephrine. As a result, it can produce several side effects. By decreasing the amount of serotonin in the brain, TBZ may increase the risk of clinical depression. Also, as a dopamine-depleting drug, TBZ can sometimes lead to Parkinsonian motor symptoms. Parkinson’s disease is the result of too little dopamine in the brain, and is characterized by rigidity and difficulty initiating movement. It is very unlikely, though, that people with HD would get Parkinsonian side effects from using TBZ, as their dopamine levels are so high. For more information on the relationship between HD and Parkinson’s disease, click here. Among people with HD who experience side effects with TBZ, most report mild symptoms such as drowsiness, constipation, insomnia (already a common occurrence in HD), akathisia, drooling, and weakness.

What research has been done on TBZ?^

TBZ has been in use in countries outside the U.S. since 1960, so many studies have been conducted on the drug.

Mikkelsen (1983) studied the tolerance of TBZ during long-term use. The results of this study showed infrequent and usually mild side effects. Only 5 of 124 participants discontinued the use of TBZ because of adverse effects. The researcher concluded that long-term treatment with TBZ appears to be quite safe.

Pearson & Reynolds (1988) linked TBZ with dopamine depletion by examining brain tissue from people with HD. They looked at people who had been treated with TBZ during their lifetimes, and compared their levels of neurotransmitters to the levels of people who had never been treated with TBZ. They found that those who had received TBZ treatment had lower concentrations of neurotransmitters in all areas of the brain that they studied, compared to those who never received TBZ treatment. These researchers found the greatest decrease of neurotransmitter was dopamine in a part of the striatum called the caudate, an area of the brain important in movement. For more information on HD and the brain, click here. However, the decrease in neurotransmitter was not limited to dopamine, but also included serotonin and similar molecules, which suggested the possibility of side effects. This study confirmed the findings of animal studies that TBZ treats chorea by depleting neurotransmitters in the brain.

Ondo, et al. (2002) tested the efficacy and tolerability of TBZ for treating chorea in 19 people with HD. Participants started with dosages of 25 milligrams per day, with a weekly increase to 150 milligrams per day. These participants had the option of not increasing the dose if they were satisfied with the results at any given stage, or if they began experiencing negative side effects at higher doses. They were evaluated at the beginning and end of the study. These evaluations included a videotaped portion, where they were rated using the motor section of the Abnormal Involuntary Movements Scale (AIMS). The videotapes showed an average improvement of 3.4 points on the AIMS (out of 42 total), with improvements attributable to TBZ in 15 of the 19 participants (two had improved before taking TBZ, one did not change, and one did not return for re-evaluation). When participants were asked to subjectively report their condition, none reported a worsening of their symptoms. Only one participant reported more than mild side effects. For this person, akathisia (feelings of restlessness and urges to move about) improved when the dose was lowered. Before taking part in this study, 13 of the 19 participants had tried at least one medication for chorea that they reported to be ineffective. All of the participants who completed this study, however, decided to continue taking TBZ to treat their chorea. The researchers concluded that TBZ is effective and well-tolerated.

Huntington Study Group (HSG) and Prestwick Pharmaceuticals (2006) collaborated on a clinical trial involving TBZ called TETRA-HD. Led by Dr. Frederick J. Marshall from the University of Rochester Medical Center, TETRA-HD is a phase III clinical trial with the goal of determining the optimal dosage of TBZ in treating chorea and other involuntary movements in people with HD. The trial was carried out at 16 different HSG sites in the United States, involving a total of 84 participants with HD. 54 of the participants were randomly assigned to receive TBZ for 12 weeks with increasing dosages over the first 7 weeks. The other 30 served as the comparison group and received a placebo. The results of the study found that TBZ is effective in treating chorea and that its side effects are less severe than those associated with other anti-choreic drugs. On the CGI Global Improvement Scale, 6.9% of the patients receiving placebo had more than minimal improvement compared to 45.1% of the patients receiving TBZ. Clinical assessments showed that TBZ was associated with drowsiness and insomnia in four patients, depressed mood in two, parkinsonism in two and akathisia in two. Most cases of adverse effects improved after adjusting dosage levels, but the risk of side effects such as increased risk of suicide, must still be acknowledged. These results confirm the benefits of TBZ usage in ameliorating the symptoms of chorea.

When will TBZ be available in the US?^

On August 15, 2008 the Food and Drug Administration (FDA) approved the first treatment for HD in the United States when federal regulators cleared Xenazine, a form of tetrabenazine made by Prestwick Pharmaceuticals Inc., for treating chorea. Although Xenazine cannot cure HD and may have harmful side effects, the FDA approval will increase the number of treatment options available to HD patients.

A series of events led up to the approval of Xenazine. The results of the TETRA-HD study were reported in October 2004 and subsequently published in the reputable, peer-reviewed journal Neurology in 2006. In April 2005, Prestwick Pharmaceuticals, the manufacturers of TBZ, announced that they had filed a New Drug Application with the FDA. The approval of this application was not expected to take long because Prestwick was granted “fast track” and orphan drug status for TBZ by the FDA. Orphan drug status is given to drugs that treat diseases that affect fewer than 200,000 people in the U.S., and the companies that produce them receive additional incentives to get them to market. In December 2007 the FDA Advisory Committee unanimously recommended Xenazine to be approved, and in August 2008 it was officially approved.

For further reading^

  • “FDA Approves First Drug for Treatment of Chorea in Huntington’s Disease” 15 Aug 2008. (http://www.fda.gov/bbs/topics/NEWS/2008/NEW01874.html) Press release from the FDA after Xenazine was approved in August 2008.
  • “FDA Approves Tetrabenazine.” 17 Aug 2008. HD Lighthouse. ( http://hdlighthouse.org/showUpdate.php?p_articleNumber=589) An article from the HD Lighthouse contributing editor commenting on the FDA approval of tetrabenazine in August 2008.
  • Huntington Study Group. “Tetrabenazine as Antichorea Therapy in Huntington Disease.” 2006. Neurology 66: 366-372 . This is the scientific article published by the Huntington Study Group discussing the TETRA-HD study and results.
  • Mikkelsen, B.O. “Tolerance of tetrabenazine during long-term treatment.” 1983. ACTA Neurologica Scandinavica 68(1):57-60. This scientific article discusses side effects of tetrabenazine and explores the possibility of long-term use.
  • Miller, Marsha. “FDA Approves Tetrabenazine.” 15 Aug 2008. Huntington’s Disease Society of America. A concise article from the HDSA summarizing key facts about tetrabenazine.
  • Ondo, et al. “Tetrabenazine Treatment for Huntington’s Disease-Associated Chorea.” 2002. Clinical Neuropharmacology 25(6):300-302. This scientific article describes a study in which the efficacy in treating chorea and tolerability of tetrabenazine were tested on people with HD.
  • Pearson, S.J. and Reynolds, G.P. “Depletion of monoamine transmitters by tetrabenazine in brain tissue in Huntington’s disease.” 1988. Neuropharmacology 27(7): 717-719. This scientific article describes a study done on brain tissue of people who had HD. It shows how those treated with tetrabenazine had reduced dopamine in their brains.

T. Wang, 2/6/09; recorded by B. Tatum, 8/21/12