Tetrabenazine

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Tetrabenazine
Tetrabenazine.svg
Tetrabenazine3d.png
Clinical data
Trade names Xenazine, Xentra, Nitoman, others
Other namesRo-1-9569
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Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Low, extensive first pass effect
Protein binding 82–85%
Metabolism Liver (CYP2D6-mediated)
Elimination half-life 10 hours parent compound (2 to 8 hours active metabolites) [3]
Excretion Kidney (~75%) and fecal (7–16%) [4]
Identifiers
  • (SS,RR)-3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.348 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H27NO3
Molar mass 317.429 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
  • O=C3C(CC(C)C)CN2C(c1c(cc(OC)c(OC)c1)CC2)C3
  • InChI=1S/C19H27NO3/c1-12(2)7-14-11-20-6-5-13-8-18(22-3)19(23-4)9-15(13)16(20)10-17(14)21/h8-9,12,14,16H,5-7,10-11H2,1-4H3 Yes check.svgY
  • Key:MKJIEFSOBYUXJB-UHFFFAOYSA-N Yes check.svgY
   (verify)

Tetrabenazine is a drug for the symptomatic treatment of hyperkinetic 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", tetrabenazine was the first approved treatment for Huntington's disease in the United States. [5] The compound has been known since the 1950s.

Contents

Medical uses

Tetrabenazine is used as a treatment, but not as a cure, for hyperkinetic disorders such as: [6] [7]

Tetrabenazine has been used as an antipsychotic in the treatment of schizophrenia, both in the past [9] [10] [11] [12] [13] [14] [15] [16] and in modern times. [17] [18] [19]

Side effects

The most common adverse reactions, 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 produce apathy. [20]

Warnings

There is a boxed warning associated with the use of tetrabenazine: [4]

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. [4]

Research

Animal model of motivational dysfunction

Tetrabenazine is used in the only animal model of motivational dysfunction. [21] [22] The drug results in selective depletion of dopamine at low doses of 0.25 to 1.0 mg/kg and induces a low-effort bias in effort-based decision-making tasks at these doses. [20] [21] [22] It has been found to reduce striatal or nucleus accumbens dopamine levels by 57 to 75% at a dose of 0.75–1.0 mg/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 10 mg/kg is needed to decrease serotonin levels as much as the reduction in dopamine levels at 1 mg/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] Dopamine D1 receptor antagonists like ecopipam and dopamine D2 receptor antagonists like haloperidol have similar amotivational effects as tetrabenazine in animals. [20] [22]

A number of pro-motivational drugs have been found to reverse the amotivational effects of tetrabenazine. [20] [21] [22] 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. [20] [21] [22] [23] [24] Selegiline shows a complicated U-shaped dose–response curve in its efficacy in the model. [21] [24] In contrast to the preceding agents, many antidepressants, 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. [20] [21] [22] [23] [24] SSRIs and NRIs actually induced further motivational impairments at high doses. [21] [23]

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]

See also

References

  1. ↑ "TETRABENAZINE RAN/TETRABENAZINE SUN/TETRABENAZINE RBX (Sun Pharma ANZ Pty Ltd)". Therapeutic Goods Administration .
  2. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  3. ↑ Yero T, Rey JA (December 2008). "Tetrabenazine (Xenazine), An FDA-Approved Treatment Option For Huntington's Disease-Related Chorea". P & T. 33 (12): 690–694. PMC   2730806 . PMID   19750050.
  4. 1 2 3 4 "Xenazine (tetrabenazine) Tablets, for Oral Use. Full Prescribing Information. Revised: 6/2015" (PDF). H. Lundbeck A/S. Retrieved 9 December 2015.
  5. ↑ 1st US drug for Huntington's disease wins approval [ dead link ]
  6. ↑ Jankovic J, Beach J (1997). "Long-term effects of tetrabenazine in hyperkinetic movement disorders". Neurology. 48 (2): 358–62. doi:10.1212/wnl.48.2.358. PMID   9040721. S2CID   33577525.
  7. ↑ 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. PMID   17133512. S2CID   22001960.
  8. ↑ Ondo WG, Hanna PA, Jankovic J (August 1999). "Tetrabenazine treatment for tardive dyskinesia: assessment by randomized videotape protocol". American Journal of Psychiatry. 156 (8): 1279–81. doi:10.1176/ajp.156.8.1279. PMID   10450276. S2CID   40131860.
  9. ↑ 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. PMID   13832091.
  10. ↑ Sacerdoti G (1960). "[First clinical experiences with tetrabenazine]" [First clinical experiences with tetrabenazine]. Rassegna di Studi Psichiatrici (in Italian). 49: 450–460. PMID   13745210.
  11. ↑ 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. PMID   13748124.
  12. ↑ 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. PMID   13684728.
  13. ↑ 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. PMID   13874731.
  14. ↑ 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. PMID   14453492.
  15. ↑ 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. PMID   14081399.
  16. ↑ 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. PMID   6007641.
  17. ↑ 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. PMID   17683910. S2CID   39312847.
  18. ↑ 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. PMID   22198452. S2CID   2649261.
  19. ↑ Kaur N, Kumar P, Jamwal S, Deshmukh R, Gauttam V (September 2016). "Tetrabenazine: Spotlight on Drug Review". Annals of Neurosciences. 23 (3): 176–185. doi:10.1159/000449184. PMC   5043267 . PMID   27721587.
  20. 1 2 3 4 5 6 7 8 9 10 Salamone JD, Correa M (January 2024). "The Neurobiology of Activational Aspects of Motivation: Exertion of Effort, Effort-Based Decision Making, and the Role of Dopamine". Annu Rev Psychol. 75: 1–32. doi:10.1146/annurev-psych-020223-012208. hdl: 10234/207207 . PMID   37788571.
  21. 1 2 3 4 5 6 7 Callaghan 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. ISBN   978-0-444-64167-0. PMID   30314570. 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.
  22. 1 2 3 4 5 6 Salamone JD, Correa M, Ferrigno S, Yang JH, Rotolo RA, Presby RE (October 2018). "The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation". Pharmacol Rev. 70 (4): 747–762. doi:10.1124/pr.117.015107. PMC   6169368 . PMID   30209181.
  23. 1 2 3 Yohn 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. PMID   27329556.
  24. 1 2 3 Contreras-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. PMID   29309800.
  25. ↑ Scalise R, Sgandurra G, Menici V, Capodagli N, Di Pietro R, Romeo DM, et al. (26 February 2021). "A Retrospective Longitudinal Study in a Cohort of Children With Dyskinetic Cerebral Palsy Treated With Tetrabenazine". Frontiers in Neurology. 12: 612429. doi: 10.3389/fneur.2021.612429 . PMID   33716922.
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