Tetrabenazine is a drug for the symptomatic treatment ofhyperkineticmovement disorders. It is sold under the brand namesNitoman andXenazine among others. On August 15, 2008, the USFood and Drug Administration (FDA) approved the use of tetrabenazine to treatchorea associated withHuntington's disease. Although other drugs had been used "off-label", tetrabenazine was the first approved treatment for Huntington's disease in the United States.[5] The compound has been known since the 1950s.
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.[4] It has also been reported to produceapathy.[20]
There is aboxed warning associated with the use of tetrabenazine:[4]
Increases the risk of depression and suicidal thoughts and behavior in patients with Huntington's disease
Balance risks of depression and suicidality with the clinical need for control of chorea when considering the use of tetrabenazine
Monitor patients for emergence or worsening of depression, suicidality or unusual changes in behavior
Inform patients, caregivers and families of the risk of depression and suicidality and instruct to report behaviours of concern promptly to the treating physician
Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation
Tetrabenazine is contraindicated in patients who are actively suicidal and in patients with untreated or inadequately treated depression[citation needed]
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 asdopamine,serotonin,norepinephrine, andhistamine from nerve terminals. Tetrabenazine reversibly inhibitsvesicular monoamine transporter 2 (VMAT2), resulting in decreased uptake of monoamines into synaptic vesicles, as well as depletion of monoamine storage.[4]
Tetrabenazine is used in the onlyanimal model ofmotivational dysfunction.[21][22] The drug results in selectivedepletion of dopamine at low doses of 0.25 to 1.0mg/kg and induces a low-effort bias in effort-based decision-making tasks at these doses.[20][21][22] It has been found to reducestriatal ornucleus accumbens dopamine levels by 57 to 75% at a dose of 0.75–1.0mg/kg in rats.[20] In contrast, levels of serotonin and norepinephrine are only reduced by up to 15 to 30% at this dosage.[20] 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.[20] 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).[20] DopamineD1 receptor antagonists likeecopipam and dopamineD2 receptor antagonists likehaloperidol have similar amotivational effects as tetrabenazine in animals.[20][22]
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.[25]
^Kenney C, Hunter C, Jankovic J (January 2007). "Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders".Movement Disorders.22 (2):193–7.doi:10.1002/mds.21222.PMID17133512.S2CID22001960.
^Smith ME (March 1960). "Clinical comparison of tetrabenazine (Ro 1-9569), reserpine and placebo in chronic schizophrenics".Diseases of the Nervous System.21 (3 Suppl):120–123.PMID13832091.
^Sacerdoti G (1960). "[First clinical experiences with tetrabenazine]" [First clinical experiences with tetrabenazine].Rassegna di Studi Psichiatrici (in Italian).49:450–460.PMID13745210.
^Schmitt W (July 1960). "[On the pharmacotherapy of psychoses: clinical research on tetrabenazine]" [On the pharmacotherapy of psychoses: clinical research on tetrabenazine].Psychiatria et Neurologia (in German).140:23–29.doi:10.1159/000131224.PMID13748124.
^Ashcroft GW, Macdougall EJ, Barker PA (March 1961). "A comparison of tetrabenazine and chlorpromazine in chronic schizophrenia".The Journal of Mental Science.107 (447):287–293.doi:10.1192/bjp.107.447.287.PMID13684728.
^Burckard E, Medhaoui M, Montigneaux P, Pfitzenmeyer J, Pfitzenmeyer H, Schaetzel JC, et al. (January 1962). "[Clinical, biological and electroencephalographic study of the action of tetrabenazine (Ro 956) in various chronic psychoses]" [Clinical, biological and electroencephalographic study of the action of tetrabenazine (Ro 956) in various chronic psychoses].Annales Médico-Psychologiques (in French).120 (1):115–119.PMID13874731.
^Kammerer T, Singer L, Geissmann P, Wetta JM (January 1962). "[Use of a new neuroleptic: tetrabenazine. Clinical, biological and electroencephalographic results]" [Use of a new neuroleptic: tetrabenazine. Clinical, biological and electroencephalographic results].Annales Médico-Psychologiques (in French).120 (1):106–115.PMID14453492.
^Lingjaerde O (1963). "Tetrabenazine (Nitoman) in the treatment of psychoses. With a discussion on the central mode of action of tetrabenazine and reserpine".Acta Psychiatrica Scandinavica.39: SUPPL170:1–SUPPL17109.PMID14081399.
^Matsumoto Y, Totsuka S, Kato M, Inoue M, Okagami K (July 1966). "[Therapy of schizophrenia with tetrabenazine]".Nihon Rinsho. Japanese Journal of Clinical Medicine (in Japanese).24 (7):1360–1364.PMID6007641.
^Malik A, Balkoski V (November 2007). "Neurotransmitter depleter tetrabenazine; potential candidate for schizophrenia treatment?".Schizophrenia Research.96 (1–3):267–268.doi:10.1016/j.schres.2007.07.010.PMID17683910.S2CID39312847.
^Remington G, Kapur S, Foussias G, Agid O, Mann S, Borlido C, et al. (February 2012). "Tetrabenazine augmentation in treatment-resistant schizophrenia: a 12-week, double-blind, placebo-controlled trial".Journal of Clinical Psychopharmacology.32 (1):95–99.doi:10.1097/JCP.0b013e31823f913e.PMID22198452.S2CID2649261.
^abcdefgCallaghan CK, Rouine J, O'Mara SM (2018). "Potential roles for opioid receptors in motivation and major depressive disorder".The Opioid System as the Interface between the Brain's Cognitive and Motivational Systems. Progress in Brain Research. Vol. 239. pp. 89–119.doi:10.1016/bs.pbr.2018.07.009.ISBN978-0-444-64167-0.PMID30314570.However, there is currently only one published animal model of motivational dysfunction, using tetrabenazine (TBZ), which is a selective inhibitor of vesicular monoamine transporter 2 (VMAT2) also known as solute carrier family 18 member 2 (SLC18A2). VMAT2 is a protein which depletes dopamine (DA), but treatment with TBZ produces depression symptoms in patients (Kenney et al., 2006). [...] Treatment of animals with the VMAT2 inhibitor TBZ induces a low effort bias or amotivational symptoms in these effort-based, decision-making tasks (Contreras-Mora et al., 2018; Nunes et al., 2013, 2014; Randall et al., 2014). [...] Administration of the monoamine oxidase B (MAO-B) inhibitor, deprenyl, has been shown to reverse the low effort bias or amotivational symptoms induced by TBZ in effort based decision-making tasks (Contreras-Mora et al., 2018). Treatment with the most common antidepressant drugs, SSRIs, fluoxetine or citalopram, does not reverse the effort based effects of TBZ and in fact produced further impairments in lever pressing (Yohn et al., 2016). Administration of a different class of antidepressant therapy, norepinephrine uptake inhibitor, desipramine, did not reverse TBZ effects either (Yohn et al., 2016). Interestingly MAO inhibitors can also be used in the treatment of depression but only irreversible MAO-B inhibitors like deprenyl, and not MAO-A inhibitors, have antidepressant effects in humans and recover TBZ effects in rodents (Contreras-Mora et al., 2018; Jang et al., 2013; Sclar et al., 2013). [...] The dose–response of deprenyl generates an inverted U-shaped dose–response curve, suggesting correct dosing is essential (Contreras-Mora et al., 2018). It is possible deprenyl is blocking both MAO-A and MAO-B at higher doses which is producing the inverted U-shaped response.
^abcYohn SE, Errante EE, Rosenbloom-Snow A, Somerville M, Rowland M, Tokarski K, et al. (October 2016). "Blockade of uptake for dopamine, but not norepinephrine or 5-HT, increases selection of high effort instrumental activity: Implications for treatment of effort-related motivational symptoms in psychopathology".Neuropharmacology.109:270–280.doi:10.1016/j.neuropharm.2016.06.018.PMID27329556.
^abcContreras-Mora H, Rowland MA, Yohn SE, Correa M, Salamone JD (March 2018). "Partial reversal of the effort-related motivational effects of tetrabenazine with the MAO-B inhibitor deprenyl (selegiline): Implications for treating motivational dysfunctions".Pharmacol Biochem Behav.166:13–20.doi:10.1016/j.pbb.2018.01.001.PMID29309800.
