Tetrabenazine#Animal model of motivational dysfunction

Tetrabenazine is used as a treatment, but not as a cure, for hyperkinetic disorders such as:{{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}}{{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}}

• Huntington's disease – specifically, the chorea associated with it
• Tourette syndrome and other tic disorders
• Tardive dyskinesia,{{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|url-access=subscription}} a serious and sometimes irreversible side effect of long-term use of many antipsychotics, mainly typical antipsychotics
• Hemiballismus, spontaneous flinging limb movements due to contra-lateral subthalamic nucleus damage

Tetrabenazine has been used as an antipsychotic in the treatment of schizophrenia, both in the past{{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 | issue = 3 Suppl | pages = 120–123 | date = March 1960 | pmid = 13832091 | doi = }}{{cite journal | vauthors = Sacerdoti G | title = [First clinical experiences with tetrabenazine] | 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 }}{{cite journal | vauthors = Schmitt W | title = [On the pharmacotherapy of psychoses: clinical research on tetrabenazine] | 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 }}{{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 }}{{cite journal | vauthors = Burckard E, Medhaoui M, Montigneaux P, Pfitzenmeyer J, Pfitzenmeyer H, Schaetzel JC, Singer L, Geissmann P | title = [Clinical, biological and electroencephalographic study of the action of tetrabenazine (Ro 956) in various chronic psychoses] | 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 }}{{cite journal | vauthors = Kammerer T, Singer L, Geissmann P, Wetta JM | title = [Use of a new neuroleptic: tetrabenazine. Clinical, biological and electroencephalographic results] | 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 }}{{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 = }}{{cite journal | vauthors = Matsumoto Y, Totsuka S, Kato M, Inoue M, Okagami K | title = [Therapy of schizophrenia with tetrabenazine] | language = Japanese | journal = Nihon Rinsho. Japanese Journal of Clinical Medicine | volume = 24 | issue = 7 | pages = 1360–1364 | date = July 1966 | pmid = 6007641 | doi = }} and in modern times.{{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 }}{{cite journal | vauthors = Remington G, Kapur S, Foussias G, Agid O, Mann S, Borlido C, Richards S, Javaid N | 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 }}{{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 }}

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.

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

• 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|date=March 2025}}

{{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 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.

{{See also|Conditioned avoidance response test#Test of other drug effects}}

Tetrabenazine is used in the only animal model of motivational dysfunction.{{cite book | vauthors = Callaghan CK, Rouine J, O'Mara SM | chapter = Potential roles for opioid receptors in motivation and major depressive disorder | title = The Opioid System as the Interface between the Brain's Cognitive and Motivational Systems | 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.}}{{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 = }} The drug results in selective depletion of dopamine 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. It has been found to reduce striatal or nucleus accumbens dopamine levels by 57 to 75% at a dose of 0.75–1.0{{nbsp}}mg/kg in rats.{{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 }} 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{{nbsp}}mg/kg is needed to decrease serotonin levels as much as the reduction in dopamine levels at 1{{nbsp}}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.

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.{{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 = }}{{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 = }} 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.

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.{{cite journal | vauthors = Scalise R, Sgandurra G, Menici V, Capodagli N, Di Pietro R, Romeo DM, Sini F, Pagliano E, Foscan M, Cioni G, Battini R | title = A Retrospective Longitudinal Study in a Cohort of Children With Dyskinetic Cerebral Palsy Treated With Tetrabenazine | language = English | journal = Frontiers in Neurology | volume = 12 | pages = 612429 | date = 26 February 2021 | pmid = 33716922 | doi = 10.3389/fneur.2021.612429 | doi-access = free | hdl = 11568/1115888 | hdl-access = free | pmc = 7953156 }}

• Deutetrabenazine

{{Reflist}}

• [http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021894s010lbl.pdf Xenazine prescribing information FDA] {{Webarchive|url=https://web.archive.org/web/20170216205253/http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021894s010lbl.pdf |date=2017-02-16 }}
• [https://web.archive.org/web/20070310235952/http://nimh-repository.rti.org/infosheet.asp?rec=200404271700320322 NIMH Repository data sheet]
• [https://archive.today/20100718025247/http://www.stanford.edu/group/hopes/treatmts/tbz/rtbz3.html "Tetrabenazine"] from HOPES: Huntington's Disease Outreach Project for Education at Stanford
• [http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20(General%20Monographs-%20N)/NITOMAN.html Detailed monograph on tetrabenazine on rxmed.com]
• [http://www.netdoctor.co.uk/medicines/100004430.html Information on tetrabenazine from netdoctor.co.uk] {{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}}

Category:Anxiogenics

Category:Antidyskinetic agents

Category:Huntington's disease

Category:Cyclic ketones

Category:Orphan drugs

Category:Phenol ethers

Category:Tardive dyskinesia

Category:Tetrahydroisoquinolines

Category:VMAT inhibitors