Tetrabenazine

Overview

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. The compound has been known since the 1950s.[1] WP

Uses, dosage and effects

Medical uses

Tetrabenazine is used as a treatment, but not as a cure, for hyperkinetic disorders such as:[2][3] WP

• Huntington's disease – specifically, the chorea associated with it[2][3] WP
• Tourette syndrome and other tic disorders[2][3] WP
• Tardive dyskinesia, a serious and sometimes irreversible side effect of long-term use of many antipsychotics, mainly typical antipsychotics[4] WP
• Hemiballismus, spontaneous flinging limb movements on one side of the body due to damage to the subthalamic nucleus on the other side[2][3] WP

Tetrabenazine has been used as an antipsychotic in the treatment of schizophrenia, both in the past and in modern times.[5–15] WP

Risks and side effects

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.[16][17] WP

Black box warning

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

• Increases the risk of depression and suicidal thoughts and behavior in patients with Huntington's disease[16] WP
• Balance risks of depression and suicidality with the clinical need for control of chorea when considering the use of tetrabenazine[16] WP
• Monitor patients for emergence or worsening of depression, suicidality or unusual changes in behavior[16] WP
• Inform patients, caregivers and families of the risk of depression and suicidality and instruct to report behaviours of concern promptly to the treating physician[16] WP
• Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation[16] WP
• Tetrabenazine is contraindicated in patients who are actively suicidal and in patients with untreated or inadequately treated depression[16] WP⚠ Wikipedia itself has flagged this text: citation needed.

Pharmacology

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] WP

Research

Animal model of motivational dysfunction

Tetrabenazine is used in the only animal model of motivational dysfunction. 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. 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. In contrast, levels of serotonin and norepinephrine are only reduced by up to 15 to 30% at this dosage. 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. 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.[17][18][19] WP

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. Selegiline shows a complicated U-shaped dose–response curve in its efficacy in the model. 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. SSRIs and NRIs actually induced further motivational impairments at high doses.[17–21] WP

Dyskinetic cerebral palsy

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] WP

Chemistry

Formula

C19H27NO3 PC

CAS number

718635-93-9 PC

Molar mass (g/mol)

317.4 PC

IUPAC name (computed by PubChem)

9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydrobenzo[a]quinolizin-2-one PC

SMILES

CC(C)CC1CN2CCC3=CC(=C(C=C3C2CC1=O)OC)OC PC

InChIKey

MKJIEFSOBYUXJB-UHFFFAOYSA-N PC

PubChem CID

6018

IUPAC name

(SS,RR)-3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido WP

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Other 1st US drug for Huntington's disease wins approval
2. Journal / agency Jankovic J, Beach J. Long-term effects of tetrabenazine in hyperkinetic movement disorders. Neurology. 1997. doi:10.1212/wnl.48.2.358 · PMID 9040721
3. Journal / agency Kenney C, Hunter C, Jankovic J. Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders. Movement Disorders. January 2007. doi:10.1002/mds.21222 · PMID 17133512
4. Journal / agency Ondo WG, Hanna PA, Jankovic J. Tetrabenazine treatment for tardive dyskinesia: assessment by randomized videotape protocol. American Journal of Psychiatry. August 1999. doi:10.1176/ajp.156.8.1279 · PMID 10450276
5. Journal / agency Smith ME. Clinical comparison of tetrabenazine (Ro 1-9569), reserpine and placebo in chronic schizophrenics. Diseases of the Nervous System. March 1960. PMID 13832091
6. Journal / agency Sacerdoti G. First clinical experiences with tetrabenazine. Rassegna di Studi Psichiatrici. 1960. PMID 13745210
7. Journal / agency Schmitt W. On the pharmacotherapy of psychoses: clinical research on tetrabenazine. Psychiatria et Neurologia. July 1960. doi:10.1159/000131224 · PMID 13748124
8. Journal / agency Ashcroft GW, Macdougall EJ, Barker PA. A comparison of tetrabenazine and chlorpromazine in chronic schizophrenia. The Journal of Mental Science. March 1961. doi:10.1192/bjp.107.447.287 · PMID 13684728
9. Journal / agency Burckard E, Medhaoui M, Montigneaux P, Pfitzenmeyer J, Pfitzenmeyer H, Schaetzel JC, Singer L, Geissmann P. Clinical, biological and electroencephalographic study of the action of tetrabenazine (Ro 956) in various chronic psychoses. Annales Médico-Psychologiques. January 1962. PMID 13874731
10. Journal / agency Kammerer T, Singer L, Geissmann P, Wetta JM. Use of a new neuroleptic: tetrabenazine. Clinical, biological and electroencephalographic results. Annales Médico-Psychologiques. January 1962. PMID 14453492
11. Journal / agency Lingjaerde O. Tetrabenazine (Nitoman) in the treatment of psychoses. With a discussion on the central mode of action of tetrabenazine and reserpine. Acta Psychiatrica Scandinavica. 1963. PMID 14081399
12. Journal / agency Matsumoto Y, Totsuka S, Kato M, Inoue M, Okagami K. Therapy of schizophrenia with tetrabenazine. Nihon Rinsho. Japanese Journal of Clinical Medicine. July 1966. PMID 6007641
13. Journal / agency Malik A, Balkoski V. Neurotransmitter depleter tetrabenazine; potential candidate for schizophrenia treatment?. Schizophrenia Research. November 2007. doi:10.1016/j.schres.2007.07.010 · PMID 17683910
14. Journal / agency Remington G, Kapur S, Foussias G, Agid O, Mann S, Borlido C, Richards S, Javaid N. Tetrabenazine augmentation in treatment-resistant schizophrenia: a 12-week, double-blind, placebo-controlled trial. Journal of Clinical Psychopharmacology. February 2012. doi:10.1097/JCP.0b013e31823f913e · PMID 22198452
15. Journal / agency Kaur N, Kumar P, Jamwal S, Deshmukh R, Gauttam V. Tetrabenazine: Spotlight on Drug Review. Annals of Neurosciences. September 2016. doi:10.1159/000449184 · PMID 27721587 · PMC5043267
16. Other Xenazine (tetrabenazine) Tablets, for Oral Use. Full Prescribing Information. Revised: 6/2015
17. Journal / agency Salamone JD, Correa M. The Neurobiology of Activational Aspects of Motivation: Exertion of Effort, Effort-Based Decision Making, and the Role of Dopamine. Annu Rev Psychol. January 2024. doi:10.1146/annurev-psych-020223-012208 · PMID 37788571
18. Journal / agency Callaghan CK, Rouine J, O'Mara SM. The Opioid System as the Interface between the Brain's Cognitive and Motivational Systems. 2018. doi:10.1016/bs.pbr.2018.07.009 · PMID 30314570
19. Journal / agency Salamone JD, Correa M, Ferrigno S, Yang JH, Rotolo RA, Presby RE. The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation. Pharmacol Rev. October 2018. doi:10.1124/pr.117.015107 · PMID 30209181 · PMC6169368
20. Journal / agency Yohn SE, Errante EE, Rosenbloom-Snow A, Somerville M, Rowland M, Tokarski K, Zafar N, Correa M, Salamone JD. 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. October 2016. doi:10.1016/j.neuropharm.2016.06.018 · PMID 27329556
21. Journal / agency Contreras-Mora H, Rowland MA, Yohn SE, Correa M, Salamone JD. 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. March 2018. doi:10.1016/j.pbb.2018.01.001 · PMID 29309800
22. Journal / agency Scalise R, Sgandurra G, Menici V, Capodagli N, Di Pietro R, Romeo DM, Sini F, Pagliano E, Foscan M, Cioni G, Battini R. A Retrospective Longitudinal Study in a Cohort of Children With Dyskinetic Cerebral Palsy Treated With Tetrabenazine. Frontiers in Neurology. 26 February 2021. doi:10.3389/fneur.2021.612429 · PMID 33716922 · PMC7953156

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