Chemistry:Tetrabenazine

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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.[1] 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:[2][3]

Tetrabenazine has been used as an antipsychotic in the treatment of schizophrenia, both in the past[5][6][7][8][9][10][11][12] and in modern times.[13][14][15]

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.[16] It has also been reported to produce apathy.[17]

Black box warning

There is a boxed warning associated with the use of tetrabenazine:[16]

  • 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

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.[16]

Research

Animal model of motivational dysfunction

Tetrabenazine is used in the only animal model of motivational dysfunction.[18][19] 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.[17][18][19] 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.[17] In contrast, levels of serotonin and norepinephrine are only reduced by up to 15 to 30% at this dosage.[17] 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.[17] 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).[17] Dopamine D1 receptor antagonists like ecopipam and dopamine D2 receptor antagonists like haloperidol have similar amotivational effects as tetrabenazine in animals.[17][19]

A number of pro-motivational drugs have been found to reverse the amotivational effects of tetrabenazine.[17][18][19] 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.[17][18][19][20][21] Selegiline shows a complicated U-shaped dose–response curve in its efficacy in the model.[18][21] 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.[17][18][19][20][21] SSRIs and NRIs actually induced further motivational impairments at high doses.[18][20]

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.[22]

See also

References

  1. ↑ 1st US drug for Huntington's disease wins approval
  2. ↑ "Long-term effects of tetrabenazine in hyperkinetic movement disorders". Neurology 48 (2): 358–62. 1997. doi:10.1212/wnl.48.2.358. PMID 9040721. 
  3. ↑ "Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders". Movement Disorders 22 (2): 193–7. January 2007. doi:10.1002/mds.21222. PMID 17133512. 
  4. ↑ "Tetrabenazine treatment for tardive dyskinesia: assessment by randomized videotape protocol". American Journal of Psychiatry 156 (8): 1279–81. August 1999. doi:10.1176/ajp.156.8.1279. PMID 10450276. http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=10450276. 
  5. ↑ "Clinical comparison of tetrabenazine (Ro 1-9569), reserpine and placebo in chronic schizophrenics". Diseases of the Nervous System 21 (3 Suppl): 120–123. March 1960. PMID 13832091. 
  6. ↑ "[First clinical experiences with tetrabenazine]" (in Italian). Rassegna di Studi Psichiatrici 49: 450–460. 1960. PMID 13745210. 
  7. ↑ "[On the pharmacotherapy of psychoses: clinical research on tetrabenazine]" (in German). Psychiatria et Neurologia 140: 23–29. July 1960. doi:10.1159/000131224. PMID 13748124. 
  8. ↑ "A comparison of tetrabenazine and chlorpromazine in chronic schizophrenia". The Journal of Mental Science 107 (447): 287–293. March 1961. doi:10.1192/bjp.107.447.287. PMID 13684728. 
  9. ↑ "[Clinical, biological and electroencephalographic study of the action of tetrabenazine (Ro 956) in various chronic psychoses]" (in French). Annales Médico-Psychologiques 120 (1): 115–119. January 1962. PMID 13874731. 
  10. ↑ "[Use of a new neuroleptic: tetrabenazine. Clinical, biological and electroencephalographic results]" (in French). Annales Médico-Psychologiques 120 (1): 106–115. January 1962. PMID 14453492. 
  11. ↑ "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. 1963. PMID 14081399. 
  12. ↑ "[Therapy of schizophrenia with tetrabenazine]" (in Japanese). Nihon Rinsho. Japanese Journal of Clinical Medicine 24 (7): 1360–1364. July 1966. PMID 6007641. 
  13. ↑ "Neurotransmitter depleter tetrabenazine; potential candidate for schizophrenia treatment?". Schizophrenia Research 96 (1–3): 267–268. November 2007. doi:10.1016/j.schres.2007.07.010. PMID 17683910. 
  14. ↑ "Tetrabenazine augmentation in treatment-resistant schizophrenia: a 12-week, double-blind, placebo-controlled trial". Journal of Clinical Psychopharmacology 32 (1): 95–99. February 2012. doi:10.1097/JCP.0b013e31823f913e. PMID 22198452. 
  15. ↑ "Tetrabenazine: Spotlight on Drug Review". Annals of Neurosciences 23 (3): 176–185. September 2016. doi:10.1159/000449184. PMID 27721587. 
  16. ↑ 16.0 16.1 16.2 Cite error: Invalid <ref> tag; no text was provided for refs named PI
  17. ↑ 17.00 17.01 17.02 17.03 17.04 17.05 17.06 17.07 17.08 17.09 "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. January 2024. doi:10.1146/annurev-psych-020223-012208. PMID 37788571. 
  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 18.6 "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. 239. 2018. pp. 89–119. doi:10.1016/bs.pbr.2018.07.009. ISBN 978-0-444-64167-0. "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." 
  19. ↑ 19.0 19.1 19.2 19.3 19.4 19.5 "The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation". Pharmacol Rev 70 (4): 747–762. October 2018. doi:10.1124/pr.117.015107. PMID 30209181. 
  20. ↑ 20.0 20.1 20.2 "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. October 2016. doi:10.1016/j.neuropharm.2016.06.018. PMID 27329556. 
  21. ↑ 21.0 21.1 21.2 "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. March 2018. doi:10.1016/j.pbb.2018.01.001. PMID 29309800. 
  22. ↑ "A Retrospective Longitudinal Study in a Cohort of Children With Dyskinetic Cerebral Palsy Treated With Tetrabenazine" (in English). Frontiers in Neurology 12. 26 February 2021. doi:10.3389/fneur.2021.612429. PMID 33716922. 



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