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Revision as of 12:31, 10 January 2012 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 467777703 of page Tetrabenazine for the Chem/Drugbox validation project (updated: '').  Latest revision as of 20:12, 14 November 2024 edit Citation bot (talk | contribs)Bots5,428,809 edits Altered template type. Add: isbn, series. | Use this bot. Report bugs. | Suggested by Whoop whoop pull up | Category:Tardive dyskinesia | #UCB_Category 1/5 
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{{short description|Medication for hyperkinetic movement disorders}}
{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
{{Drugbox {{Drugbox
⚫ | verifiedrevid = 470603336
| Watchedfields = changed
⚫ | verifiedrevid = 419296654
| IUPAC_name = (''SS'',''RR'')-3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyridoisoquinolin-2-one | IUPAC_name = (''SS'',''RR'')-3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyridoisoquinolin-2-one
| image = (RR,SS)-Tetrabenazine Structural Formulae.png<!-- stereochemistry??? --> | image = Tetrabenazine.svg
| image2 = Tetrabenazine3d.png | image2 = Tetrabenazine3d.png
| imagename = 1 : 1 mixture (racemate) | chirality = ]
| drug_name = Tetrabenazine


<!--Clinical data--> <!--Clinical data-->
| tradename = Xenazine | tradename = Xenazine, Xentra, Nitoman, others
| Drugs.com = {{drugs.com|CDI|tetrabenazine}} | Drugs.com = {{drugs.com|CDI|tetrabenazine}}
| pregnancy_AU = B3
| pregnancy_category = C
⚫ | routes_of_administration = ]
| legal_status = ℞-only (US)

⚫ | routes_of_administration = Oral (tablets, 25&nbsp;mg)
| legal_AU = S4
| legal_AU_comment = <ref>{{cite web|url=https://www.tga.gov.au/resources/prescription-medicines-registrations/tetrabenazine-rantetrabenazine-suntetrabenazine-rbx-sun-pharma-anz-pty-ltd|title=TETRABENAZINE RAN/TETRABENAZINE SUN/TETRABENAZINE RBX (Sun Pharma ANZ Pty Ltd)|website=]}}</ref>
| legal_BR = C1
| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=] |language=pt-BR |publication-date=2023-04-04}}</ref>
| legal_US = Rx-only


<!--Pharmacokinetic data--> <!--Pharmacokinetic data-->
| bioavailability = Low, extensive ] | bioavailability = Low, extensive ]
| protein_bound = 82–85% | protein_bound = 82–85%
| metabolism = ] (]-mediated) | metabolism = ] (]-mediated)
| elimination_half-life = 10 hours parent compound (2 to 8 hours active metabolites)<ref name=hl>{{cite journal | vauthors = Yero T, Rey JA | title = Tetrabenazine (Xenazine), An FDA-Approved Treatment Option For Huntington's Disease-Related Chorea | journal = P & T | volume = 33 | issue = 12 | pages = 690–694 | date = December 2008 | pmid = 19750050 | pmc = 2730806 }}</ref>
| excretion = ] and fecal
| excretion = ] (~75%) and fecal (7–16%)<ref name=PI>{{cite web|title=Xenazine (tetrabenazine) Tablets, for Oral Use. Full Prescribing Information. Revised: 6/2015|url=http://www.lundbeck.com/upload/us/files/pdf/Products/Xenazine_PI_US_EN.pdf|publisher=H. Lundbeck A/S|access-date=9 December 2015}}</ref>


<!--Identifiers--> <!--Identifiers-->
| IUPHAR_ligand = 4834
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}} | CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 58-46-8 | CAS_number = 58-46-8
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<!--Chemical data--> <!--Chemical data-->
| C=19 | H=27 | N=1 | O=3 | C=19 | H=27 | N=1 | O=3
| molecular_weight = 317.427 g/mol
| smiles = O=C3C(CC(C)C)CN2C(c1c(cc(OC)c(OC)c1)CC2)C3 | smiles = O=C3C(CC(C)C)CN2C(c1c(cc(OC)c(OC)c1)CC2)C3
| InChI = 1/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
| InChIKey = MKJIEFSOBYUXJB-UHFFFAOYAN
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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 | StdInChI = 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
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| synonyms = Ro-1-9569 | synonyms = Ro-1-9569
}} }}

'''Tetrabenazine''' is a drug for the symptomatic treatment of ] ]. It is sold under the brand names '''Nitoman''' and '''Xenazine''' among others. On August 15, 2008, the U.S. ] approved the use of tetrabenazine to treat ] associated with ]. Although other drugs had been used "]," tetrabenazine was the first approved treatment for Huntington's disease in the U.S.<ref> {{dead link|date=May 2016|bot=medic}}{{cbignore|bot=medic}}</ref> The compound has been known since the 1950s.

==Medical uses==
Tetrabenazine is used as a treatment, but not as a ], for hyperkinetic disorders such as:<ref name="JankovicHyperkinectic">{{cite journal|vauthors=Jankovic J, Beach J |title=Long-term effects of tetrabenazine in hyperkinetic movement disorders|journal=Neurology|volume=48|issue=2|pages=358–62|year=1997|pmid=9040721|doi=10.1212/wnl.48.2.358|s2cid=33577525}}</ref><ref name="pmid17133512">{{cite journal|vauthors=Kenney C, Hunter C, Jankovic J |title=Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders|journal=Movement Disorders|volume=22|issue=2|pages=193–7|date=January 2007|pmid=17133512|doi=10.1002/mds.21222|s2cid=22001960}}</ref>

* ] – specifically, the ] associated with it
* ] and other ]s
* ],<ref name="pmid10450276">{{cite journal|vauthors=Ondo WG, Hanna PA, Jankovic J |title=Tetrabenazine treatment for tardive dyskinesia: assessment by randomized videotape protocol|journal=American Journal of Psychiatry|volume=156|issue=8|pages=1279–81|date=August 1999|pmid=10450276|doi=10.1176/ajp.156.8.1279|s2cid=40131860 |url=http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=10450276}}</ref> a serious and sometimes irreversible side effect of long-term use of many antipsychotics, mainly ]s
* ], spontaneous flinging limb movements due to contra-lateral ] damage

Tetrabenazine has been used as an ] in the treatment of ], both in the past<ref name="pmid13832091">{{cite journal | vauthors = Smith ME | title = Clinical comparison of tetrabenazine (Ro 1-9569), reserpine and placebo in chronic schizophrenics | journal = Diseases of the Nervous System | volume = 21(3)Suppl | issue = 3 Suppl | pages = 120–123 | date = March 1960 | pmid = 13832091 | doi = }}</ref><ref name="pmid13745210">{{cite journal | vauthors = Sacerdoti G | title = | language = Italian | journal = Rassegna di Studi Psichiatrici | volume = 49 | issue = | pages = 450–460 | date = 1960 | pmid = 13745210 | doi = | trans-title = First clinical experiences with tetrabenazine }}</ref><ref name="pmid13748124">{{cite journal | vauthors = Schmitt W | title = | language = German | journal = Psychiatria et Neurologia | volume = 140 | issue = | pages = 23–29 | date = July 1960 | pmid = 13748124 | doi = 10.1159/000131224 | trans-title = On the pharmacotherapy of psychoses: clinical research on tetrabenazine }}</ref><ref name="pmid13684728">{{cite journal | vauthors = Ashcroft GW, Macdougall EJ, Barker PA | title = A comparison of tetrabenazine and chlorpromazine in chronic schizophrenia | journal = The Journal of Mental Science | volume = 107 | issue = 447 | pages = 287–293 | date = March 1961 | pmid = 13684728 | doi = 10.1192/bjp.107.447.287 }}</ref><ref name="pmid13874731">{{cite journal | vauthors = Burckard E, Medhaoui M, Montigneaux P, Pfitzenmeyer J, Pfitzenmeyer H, Schaetzel JC, Singer L, Geissmann P | display-authors = 6 | title = | language = French | journal = Annales Médico-Psychologiques | volume = 120 | issue = 1 | pages = 115–119 | date = January 1962 | pmid = 13874731 | doi = | trans-title = Clinical, biological and electroencephalographic study of the action of tetrabenazine (Ro 956) in various chronic psychoses }}</ref><ref name="pmid14453492">{{cite journal | vauthors = Kammerer T, Singer L, Geissmann P, Wetta JM | title = | language = French | journal = Annales Médico-Psychologiques | volume = 120 | issue = 1 | pages = 106–115 | date = January 1962 | pmid = 14453492 | doi = | trans-title = Use of a new neuroleptic: tetrabenazine. Clinical, biological and electroencephalographic results }}</ref><ref name="pmid14081399">{{cite journal | vauthors = Lingjaerde O | title = Tetrabenazine (Nitoman) in the treatment of psychoses. With a discussion on the central mode of action of tetrabenazine and reserpine. | journal = Acta Psychiatrica Scandinavica | volume = 39 | issue = | pages = SUPPL170:1–SUPPL17109 | date = 1963 | pmid = 14081399 | doi = }}</ref><ref name="pmid6007641">{{cite journal | vauthors = Matsumoto Y, Totsuka S, Kato M, Inoue M, Okagami K | title = | language = Japanese | journal = Nihon Rinsho. Japanese Journal of Clinical Medicine | volume = 24 | issue = 7 | pages = 1360–1364 | date = July 1966 | pmid = 6007641 | doi = }}</ref> and in modern times.<ref name="pmid17683910">{{cite journal | vauthors = Malik A, Balkoski V | title = Neurotransmitter depleter tetrabenazine; potential candidate for schizophrenia treatment? | journal = Schizophrenia Research | volume = 96 | issue = 1–3 | pages = 267–268 | date = November 2007 | pmid = 17683910 | doi = 10.1016/j.schres.2007.07.010 | s2cid = 39312847 }}</ref><ref name="pmid22198452">{{cite journal | vauthors = Remington G, Kapur S, Foussias G, Agid O, Mann S, Borlido C, Richards S, Javaid N | display-authors = 6 | title = Tetrabenazine augmentation in treatment-resistant schizophrenia: a 12-week, double-blind, placebo-controlled trial | journal = Journal of Clinical Psychopharmacology | volume = 32 | issue = 1 | pages = 95–99 | date = February 2012 | pmid = 22198452 | doi = 10.1097/JCP.0b013e31823f913e | s2cid = 2649261 }}</ref><ref name="pmid27721587">{{cite journal | vauthors = Kaur N, Kumar P, Jamwal S, Deshmukh R, Gauttam V | title = Tetrabenazine: Spotlight on Drug Review | journal = Annals of Neurosciences | volume = 23 | issue = 3 | pages = 176–185 | date = September 2016 | pmid = 27721587 | pmc = 5043267 | doi = 10.1159/000449184 }}</ref>

==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, ], anxiety, and nausea.<ref name=PI/> It has also been reported to produce ].<ref name="SalamoneCorrea2024" />

==Warnings==
There is a ] associated with the use of tetrabenazine:<ref name=PI/>

* 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

==Pharmacology==
{{See also|Monoamine-depleting agent}}

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 ], ], ], and ] from nerve terminals. Tetrabenazine reversibly inhibits ], resulting in decreased uptake of monoamines into synaptic vesicles, as well as depletion of monoamine storage.<ref name=PI/>

==Research==
===Animal model of motivational dysfunction===
{{See also|Conditioned avoidance response test#Test of other drug effects}}

Tetrabenazine is used in the only ] of ].<ref name="CallaghanRouineO'Mara2018">{{cite book | vauthors = Callaghan CK, Rouine J, O'Mara SM | title = Potential roles for opioid receptors in motivation and major depressive disorder | journal = Prog Brain Res | series = Progress in Brain Research | volume = 239 | issue = | pages = 89–119 | date = 2018 | pmid = 30314570 | doi = 10.1016/bs.pbr.2018.07.009 | isbn = 978-0-444-64167-0 | url = | quote = 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.}}</ref><ref name="SalamoneCorreaFerrigno2018">{{cite journal | vauthors = Salamone JD, Correa M, Ferrigno S, Yang JH, Rotolo RA, Presby RE | title = The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation | journal = Pharmacol Rev | volume = 70 | issue = 4 | pages = 747–762 | date = October 2018 | pmid = 30209181 | pmc = 6169368 | doi = 10.1124/pr.117.015107 | url = }}</ref> The drug results in selective ] at low doses of 0.25 to 1.0{{nbsp}}mg/kg and induces a low-effort bias in effort-based decision-making tasks at these doses.<ref name="SalamoneCorrea2024" /><ref name="CallaghanRouineO'Mara2018" /><ref name="SalamoneCorreaFerrigno2018" /> It has been found to reduce ] or ] dopamine levels by 57 to 75% at a dose of 0.75–1.0{{nbsp}}mg/kg in rats.<ref name="SalamoneCorrea2024">{{cite journal | vauthors = Salamone JD, Correa M | title = The Neurobiology of Activational Aspects of Motivation: Exertion of Effort, Effort-Based Decision Making, and the Role of Dopamine | journal = Annu Rev Psychol | volume = 75 | issue = | pages = 1–32 | date = January 2024 | pmid = 37788571 | doi = 10.1146/annurev-psych-020223-012208 | url = | hdl = 10234/207207 | hdl-access = free }}</ref> In contrast, levels of serotonin and norepinephrine are only reduced by up to 15 to 30% at this dosage.<ref name="SalamoneCorrea2024" /> A 10-fold higher dosage of 10{{nbsp}}mg/kg is needed to decrease serotonin levels as much as the reduction in dopamine levels at 1{{nbsp}}mg/kg.<ref name="SalamoneCorrea2024" /> 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., ]).<ref name="SalamoneCorrea2024" /> Dopamine ] antagonists like ] and dopamine ] antagonists like ] have similar amotivational effects as tetrabenazine in animals.<ref name="SalamoneCorrea2024" /><ref name="SalamoneCorreaFerrigno2018"/>

A number of ]s have been found to reverse the amotivational effects of tetrabenazine.<ref name="SalamoneCorrea2024" /><ref name="CallaghanRouineO'Mara2018" /><ref name="SalamoneCorreaFerrigno2018" /> These include the ] ], the ]s ], ], ], ], ], and ], and the ] and ] ].<ref name="SalamoneCorrea2024" /><ref name="CallaghanRouineO'Mara2018" /><ref name="SalamoneCorreaFerrigno2018" /><ref name="YohnErranteRosenbloom-Snow2016">{{cite journal | vauthors = Yohn SE, Errante EE, Rosenbloom-Snow A, Somerville M, Rowland M, Tokarski K, Zafar N, Correa M, Salamone JD | title = 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 | journal = Neuropharmacology | volume = 109 | issue = | pages = 270–280 | date = October 2016 | pmid = 27329556 | doi = 10.1016/j.neuropharm.2016.06.018 | url = }}</ref><ref name="Contreras-MoraRowlandYohn2018">{{cite journal | vauthors = Contreras-Mora H, Rowland MA, Yohn SE, Correa M, Salamone JD | title = Partial reversal of the effort-related motivational effects of tetrabenazine with the MAO-B inhibitor deprenyl (selegiline): Implications for treating motivational dysfunctions | journal = Pharmacol Biochem Behav | volume = 166 | issue = | pages = 13–20 | date = March 2018 | pmid = 29309800 | doi = 10.1016/j.pbb.2018.01.001 | url = }}</ref> Selegiline shows a complicated ] ] in its efficacy in the model.<ref name="CallaghanRouineO'Mara2018" /><ref name="Contreras-MoraRowlandYohn2018" /> In contrast to the preceding agents, many ]s, including ]s (SSRIs) like ] and ], the ]s (NRIs) ] and ], the selective ] ], and the non-selective ] ], are ineffective in reversing tetrabenazine-induced amotivational symptoms.<ref name="SalamoneCorrea2024" /><ref name="CallaghanRouineO'Mara2018" /><ref name="SalamoneCorreaFerrigno2018" /><ref name="YohnErranteRosenbloom-Snow2016" /><ref name="Contreras-MoraRowlandYohn2018" /> SSRIs and NRIs actually induced further motivational impairments at high doses.<ref name="CallaghanRouineO'Mara2018" /><ref name="YohnErranteRosenbloom-Snow2016" />

==See also==
* ]

==References==
{{Reflist}}

==External links==
* {{Webarchive|url=https://web.archive.org/web/20170216205253/http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021894s010lbl.pdf |date=2017-02-16 }}
*
* from ]: Huntington's Disease Outreach Project for Education at Stanford
*
* {{Webarchive|url=https://web.archive.org/web/20120104062622/http://www.netdoctor.co.uk/medicines/100004430.html |date=2012-01-04 }}

{{Antipsychotics}}
{{Other nervous system drugs}}
{{Monoamine reuptake inhibitors}}

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