Kim Ehrhard, PharmD Candidate 2019: UMKC School of Pharmacy
Ben Miskle, PharmD Candidate 2018: UMKC School of Pharmacy
Steve Stoner, PharmD, BCPP: UMKC School of Pharmacy
It is estimated that there are about five million people currently taking antipsychotic medications and that number is continuing to rise as the use of antipsychotics has expanded beyond use for schizophrenia and are now used in bipolar disorder and major depression.1 Adherence is critically important with antipsychotic treatment and a consistent barrier to medication adherence has been some concern over long-term consequences of side effects. One of those concerns has been the potential for developing tardive dyskinesia (TD), which can be described as an involuntary, repetitive, purposeless movement, typically of the tongue, jaw, lips, face, trunk, or upper extremities.2 This side effect is thought to be caused by medications that work through dopamine receptor blockade, which include antipsychotic medications and gastrointestinal medications, such as metoclopramide.2,3 It is estimated that at least 1 in 10 patients exposed to antipsychotics has TD.1 A common assessment tool for TD is the 12-item Abnormal Involuntary Movement Scale (AIMS). Administration of this scale helps to identify the level of severity of the involuntary movements. An AIMS score of at least two, in two or more body regions, or a score of three to four, in at least one body region, in a patient with at least three months of cumulative antipsychotic drug exposure, equates to a probable diagnosis of TD.4 Until recently, if TD was not caught and addressed early it was thought to be irreversible. However, in 2017 the FDA approved two new medications indicated for the treatment of TD. These two medications, deutetrabenazine (Austedo™) and valbenazine (Ingrezza™) are similar in their primary mechanisms of action, but also possess distinct differences that should be considered.
Mechanism of ActionThe exact mechanism of deutetrabenazine and valbenazine is unknown, though they likely exhibit their effects through reversible vesicular monoamine transporter 2 (VMAT2) inhibition.7,9 VMAT2 plays a key role in dopamine signaling as it is a transporter protein found in the presynaptic neurons of the CNS and helps package monoamines into synaptic vesicles for release within the synaptic cleft. TD is thought to be associated with prolonged exposure to dopamine receptor blocking agents and subsequent hyperactive dopamine signaling. This is thought to cause upregulation and hypersensitivity in postsynaptic dopamine D2 receptors in one of the areas of the brain that controls motor function.5,6 With deutetrabenazine and valbenazine selectively inhibiting the VMAT2 receptor, these medications are thought to provide reversible reductions of dopamine reuptake within the vesicle leading to a reduced number of monoamines available to bind hypersensitive postsynaptic dopamine D2 receptors.7,9
Dosing/Drug InteractionsDeutetrabenazine – The initial dose of deutetrabenazine is 6 mg twice daily for tardive dyskinesia. The dose may be increased weekly based on response and tolerability in increments of 6mg/day to a maximum of 48mg/day. With a total daily dose ≥12mg, administer in two divided doses and give with food. There are potential drug interactions to consider with deutetrabenazine. Deutetrabenazine is a substrate of CYP1A2, CYP2D6, and CYP3A4. In combination with strong CYP2D6 inhibitors like paroxetine, fluoxetine, bupropion, and quinidine, as well as poor CYP2D6 metabolizers, a maximum dose of 18mg/dose or 36mg/day should be utilized.8 Deutetrabenazine use should also be avoided with MAOIs.
Valbenazine - The initial dose for valbenazine is 40 mg once daily. After one week, the dose should be increased to the recommended dose of 80mg once daily. Continuation of 40mg once daily may be considered for some patients. Valbenazine may be taken with or without food. There are important considerations to make when putting a patient on valbenazine including drug interactions. Valbenazine and its active metabolite are metabolized via CYP3A4 and CYP2D6. It is recommended that valbenazine be avoided in use with CYP3A4 inducers as concomitant may decrease the exposure of valbenazine and its active metabolite. Some examples of CYP3A4 inducers are rifampin, carbamazepine, and phenytoin. Dose reductions are also recommended during concomitant use with CYP2D6 and CYP3A4 inhibitors. Valbenazine should also not be used with any MAOIs.10
There are some major warnings that come with each medication that need to be taken into account. Deutetrabenazine has the potential adverse effect of QT prolongation and should be adjusted with patients taking strong CYP2D6 inhibitors as well as those who are poor CYP2D6 metabolizers. Somnolence, diarrhea, fatigue, and xerostomia have shown to be the most prolific adverse effects associated with deutetrabenazine. One particular important side effect with deutetrabenazine is the black box warning for depression and suicidality in patients with Huntington’s Disease. Caution should be used in treating patients with a history of depression or prior suicide ideation. Deutetrabenazine is contraindicated in patients with untreated or inadequately treated depression.7-10
With valbenazine, the major adverse effects include somnolence and QT prolongation. Due to somnolence, it is important that the patient avoids operating heavy machinery or activities that require them to be alert while taking this medication. Even though QT prolongation is a precaution to look at, the degree of QT prolongation is not clinically significant at concentrations expected with recommended dosing.10 Dose adjustments should be made in the situation of patients with congenital long QT syndrome, patients with arrhythmias, as well as patients on strong CYP3A4 or CYP2D6 inhibitors and poor CYP2D6 metabolizers.
Clinical SignificanceDeutetrabenazine – The ARM-TD study was a randomized, double-blind, placebo-controlled, parallel group study designed to assess the safety and efficacy of deutetrabenazine over the course of 12-weeks. This trial included patients who had been diagnosed with TD for ≥3 months before screening and an AIMS motor score ≥6 (using a modified AIMS scale) at both screening and baseline, verified by a blinded central rater, with the baseline AIMS score of 9.6. The primary efficacy endpoint was the change in AIMS dyskinesia total score from baseline to week 12 as assessed by two blinded central video raters. Patients were randomized to deutetrabenazine 6mg twice daily or matching placebo with alpha set at 0.05. Deutetrabenazine was titrated weekly by 6mg until adequate dyskinesia control was achieved, a significant adverse effect occurred, or the maximal allowable dose of 48mg/day was achieved. Deutetrabenazine was found to be superior to placebo with a reduction of 3.4 points in the AIMS score for deutetrabenazine (p=0.027).11
Valbenazine - The KINECT 3 study was a randomized, double-blind, placebo-controlled trial designed to assess the safety and efficacy of valbenazine. This trial included patients with moderate to severe tardive dyskinesia as determined by clinical observation and an underlying diagnosis of schizophrenia, schizoaffective disorder, or a mood disorder, with a baseline AIMS score of 10. The primary efficacy endpoint was the mean change from baseline in the AIMS dyskinesia total score at the end of Week 6 when patients were given fixed doses of valbenazine 40 mg, valbenazine 80 mg, or placebo with alpha set at 0.05.
The valbenazine 80 mg group was found to be statistically significant with a 3.2 point reduction in the total AIMS score compared to placebo (P<0.001).12 These results are also found to be clinically significant as a change of 3 in the AIMS score can significantly improve a patient’s quality of life.13 It is important to note that longer trials are necessary to understand the long-term effects of deutetrabenazine and valbenazine in patients with tardive dyskinesia, as well as trials comparing the efficacy of deutetrabenazine in comparison with valbenazine for treatment of TD.
Role in TherapyBoth deutetrabenazine and valbenazine have been shown to be effective in treating TD, a once thought incurable side-effect of antipsychotic therapy. For patients whose TD is not improved by a reduced dosage of antipsychotic medication or a change in antipsychotic therapy, the VMAT2 inhibitors provide a potential treatment option for TD.
1. Cloud LJ, Zutshi D, Factor SA. Tardive dyskinesia: therapeutic options for an increasingly common disorder. Neurotherapeutics. 2014;11(1):166-176
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013:712
3. Kenney C, Hunter C, Davidson A, et al. Metoclopramide, an increasingly recognized cause of tardive dyskinesia. J Clin Pharmacol. 2008;48(3):379-384.
4. Guy W. ECDEU Assessment Manual for Psychopharmacology. Washington DC: US Department of Health, Education and Welfare; 1976. pp. 534–7.
5. Stahl SM. Essential Psychopharmacology Online. Based on: Stahl SM. Stahl’s Essential Psychopharmacology. 4th ed. Cambridge, UK: Cambridge University Press; 2013. http://stahlonline.cambridge.org/essential_4th_chapter.jsf?page=chapter5_introduction.htm&name=Chapter%205&title=Conventional%20antipsychotics#c02598-5-1. Accessed January 2nd, 2018
6. Sayers AC, Bürki HR, Ruch W, et al. Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias: effects of clozapine, haloperidol, loxapine and chlorpromazine. Psychopharmacologia. 1975;41(2):97-104.
7. Deutetrabenazine. Lexi-Drugs Online. Hudson (OH): Lexi-Comp, Inc. 1978-2015 [cited 2018 Jan 4]. Available from: https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6454757
8. Austedo (deutetrabenazine)[package insert]. Teva Pharmaceuticals USA, Inc., North Wales, PA;2017.
9. Valbenazine. Lexi-Drugs Online. Hudson (OH): Lexi-Comp, Inc. 1978-2015 [cited 2018 Jan 4]. Available from: https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6463109
10. Ingrezza (valbenazine)[package insert]. Neurocrine Biosciences, Inc,, San Diego, CA;2017.
11. Fernandez H, Factor S, Hauser R, et al. Randomized Controlled Trial of Deutetrabenazine for Tardive Dyskinesia. Am J Neurol. 2017;88:2003-2010.
12. Hauser R, Factor S, Marder S, et al. KINECT 3: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Valbenazine for Tardive Dyskinesia. Am J Psychiatry. 2017;174:476-484.
13. Stacy M, Kurlan R, Burke J, Siegert S, Liang G, O’Brien C. An MCID for AIMS Dyskinesia Total Score Change in Subjects with Tardive Dyskinesia. Mov Disord. 2017; 32 (suppl 2).