Tetrabenazine is a drug for the symptomatic treatment of Hyperkinesia movement disorders. It is sold under the brand names Nitoman and Xenazine among others. On August 15, 2008, the US Food and Drug Administration (FDA) approved the use of tetrabenazine to treat chorea associated with Huntington's disease. Although other drugs had been used "Off-label use", tetrabenazine was the first approved treatment for Huntington's disease in the United States.[ 1st US drug for Huntington's disease wins approval ] The compound has been known since the 1950s.
Medical uses
Tetrabenazine is used as a treatment, but not as a
cure, for hyperkinetic disorders such as:
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Huntington's disease – specifically, the chorea associated with it
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Tourette syndrome and other
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Tardive dyskinesia,
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Hemiballismus, spontaneous flinging limb movements due to contra-lateral subthalamic nucleus damage
Tetrabenazine has been used as an antipsychotic in the treatment of schizophrenia, both in the past
Adverse effects
The most common adverse effects, which have occurred in at least 10% of subjects in studies and at least 5% greater than in subjects who received placebo, have been: sedation or somnolence, fatigue, insomnia, depression, suicidal thoughts,
akathisia, anxiety, and nausea.
[ It has also been reported to produce apathy.][
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Black box warning
There is a boxed warning associated with the use of tetrabenazine:[
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Increases the risk of depression and suicidal thoughts and behavior in patients with Huntington's disease
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Balance risks of depression and suicidality with the clinical need for control of chorea when considering the use of tetrabenazine
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Monitor patients for emergence or worsening of depression, suicidality or unusual changes in behavior
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Inform patients, caregivers and families of the risk of depression and suicidality and instruct to report behaviours of concern promptly to the treating physician
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Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation
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Tetrabenazine is contraindicated in patients who are actively suicidal and in patients with untreated or inadequately treated depression
Pharmacology
The precise mechanism of action of tetrabenazine is unknown. Its anti-chorea effect is believed to be due to a reversible depletion of monoamines such as dopamine, serotonin, norepinephrine, and histamine from nerve terminals. Tetrabenazine reversibly inhibits vesicular monoamine transporter 2 (VMAT2), resulting in decreased uptake of monoamines into synaptic vesicles, as well as depletion of monoamine storage.[
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Research
Animal model of motivational dysfunction
Tetrabenazine is used in the only animal model of amotivation.[ It has been found to reduce striatum or nucleus accumbens dopamine levels by 57 to 75% at a dose of 0.75–1.0mg/kg in rats.][ A 10-fold higher dosage of 10mg/kg is needed to decrease serotonin levels as much as the reduction in dopamine levels at 1mg/kg.][ The low-effort bias of systemic administration of tetrabenazine also occurs when it is injected directly into the nucleus accumbens but not the overlying medial neostriatum (i.e., dorsal striatum).][ Dopamine D1 receptor antagonists like ecopipam and dopamine D2 receptor antagonists like haloperidol have similar amotivational effects as tetrabenazine in animals.][
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A number of pro-motivational drugs have been found to reverse the amotivational effects of tetrabenazine.[ These include the dopamine releasing agent lisdexamfetamine, the dopamine reuptake inhibitors methylphenidate, bupropion, modafinil, vanoxerine, PRX-14040, and MRZ-9547, and the MAO-B inhibitor and catecholaminergic activity enhancer selegiline.][ In contrast to the preceding agents, many , including selective serotonin reuptake inhibitors (SSRIs) like fluoxetine and citalopram, the norepinephrine reuptake inhibitors (NRIs) desipramine and atomoxetine, the selective MAO-A inhibitor moclobemide, and the non-selective monoamine oxidase inhibitor pargyline, are ineffective in reversing tetrabenazine-induced amotivational symptoms.][ SSRIs and NRIs actually induced further motivational impairments at high doses.][
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A retrospective longitudinal study in a cohort of 23 children with dyskinetic cerebral palsy was conducted where they were treated with tetrabenazine. Results showed significant improvement in movement disorders over time. The study supports tetrabenzine's potential for DCP treatment and shows that the MD-CRS 4-18 scale is a tool for tracking progress in future clinical trials.
See also
External links
