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Choosing the Right VMAT2 Inhibitor for TD

Sanjay Gupta, MD

Clinical Professor
Department of Psychiatry
SUNY at Buffalo Jacobs School of Medicine
Chief Medical Officer
BryLin Behavioral Health System
Buffalo, New York


Sanjay Gupta, MD, has disclosed that he has received consulting fees from Intra-Cellular and fees for non-CME/CE services from AbbVie, Alkermes, Intra-Cellular, Janssen, Neurocrine, Otsuka, and Sunovion.


View ClinicalThoughts from this Author

Released: November 19, 2021

Updated: March 3, 2022

Making a Choice of FDA-Approved Agents to Treat Tardive Dyskinesia: What Should We Consider?

The availability of 2 FDA-approved agents for the treatment of tardive dyskinesia (TD) has been a tremendous accomplishment for the care of our patients.1 TD was first described by Schonecker in 1957 and had no validated treatments until the approval of valbenazine and deutetrabenazine in 2017.2 We used everything and the kitchen sink to treat this antipsychotic-induced adverse event. Anticholinergic agents (eg, benztropine, trihexyphenidyl) are commonly used to treat TD even at this time, but they cause cognitive and functional impairment in individuals with schizophrenia and increase the risk of delirium in older adults.

More patients with schizophrenia are now receiving second-generation antipsychotics (SGA), and in the United States, there has been a sharp increase in the use of SGAs for the treatment of bipolar disorder whereas use of mood stabilizers and lithium has declined.3,4 In addition, the SGAs (eg, aripiprazole, olanzapine, quetiapine) have been widely used for the augmentation of antidepressants to treat major depressive disorder. Schizophrenia accounts for only 23% of the atypical antipsychotic use in the United States. Data from the National Health and Nutrition Examination Survey 2013-2018 estimated the prevalence of antipsychotic use among US adults was 1.6%. In 2020, it translated into 5 million prescriptions. The rates of TD are lower with SGAs but still stand at 7.2% prevalence with no previous SGA exposure. We expect to see a higher total number of patients with TD due to the high use of antipsychotics, especially in those with mood and anxiety disorders, because these individuals are also at a greater risk of TD.

Treatments are:

  • Level A: VMAT2 inhibitors (valbenazine, deutetrabenazine) effective for the treatment of TD
  • Level B: clonazepam (one study), ginkgo biloba extract Egb-361 (one study)
  • Level C: amantadine (3 studies, 2 double blind), tetrabenazine (multiple studies, few placebo controlled)

For treatment-resistant cases, globus pallidus interna deep brain stimulation is level C evidence. There is insufficient evidence for switching from first-generation antipsychotics to SGAs for the treatment of TD (level U) 5.

Clinical Use and Titration
The titration of valbenazine starts with a dosage of 40 mg/day and increased to 80 mg/day in 7 days, which is the therapeutic dosage. The administration of valbenazine is not dependent on food intake and is dosed once daily. Recently, a 60-mg dose has become available for those who may have tolerability issues with the 80-mg dose of valbenazine. Deutetrabenazine is started at 6 mg twice daily with food and increased by 6 mg weekly to a maximum dosage of 24 mg by mouth twice daily.6,7

Monitoring ECG
Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.7 In my opinion, when the patient is receiving concomitant medications known to cause QT prolongation, the QT interval should be assessed before and after increasing the dose of deutetrabenazine or of the medication known to cause QT prolongation to be on the safer side.

Efficacy Comparison
There are currently no well-designed head-to-head prospective comparison studies between deutetrabenazine and valbenazine. Aggarwal and colleagues8 conducted an indirect treatment comparison (ITC). The data for both drugs were compared by trial and dose, and outcomes were analyzed at multiple time points. Valbenazine 40 mg/day was statistically similar to all doses of deutetrabenazine at all time points. The Abnormal Involuntary Movement Scale (AIMS) scores improvement significantly with valbenazine 80 mg/day at 6 weeks v deutetrabenazine 36 mg/day at 8 weeks. The VMAT2 occupancy of deutetrabenazine increases with dosage. The highest VMAT2 occupancy of valbenazine 80 mg/day is higher than deutetrabenazine 48 mg/day. The VMAT occupancy of valbenazine 40 mg/day of is similar to deutetrabenazine 48 mg/day.

The Cost Factor
The indirect comparison based on treatment over 1 year used 3 outcome measures:

  1. 50% improvement over baseline in AIMS score
  2. Response at 1 year using Clinical Global Impression of change score ≤2
  3. Health outcomes including quality-adjusted life-years

Using the AIMS response, the incremental cost-effectiveness ratio was $9951/quality-adjusted life-years for valbenazine compared with deutetrabenazine. Based on this meta-analysis, valbenazine iscost-effective for the treatment of TD compared with deutetrabenazine.9

Considering all of the above factors, valbenazine would be my preferred choice for treating TD, though there may be some circumstances that make deutetrabenazine the more appropriate choice for the patient. Currently, there are no predictors of a better response to deutetrabenazine or valbenazine.

Reference

  1. Rakesh G, Muzyk A, Szabo ST, et al. Tardive dyskinesia: 21st century may bring new treatments to a forgotten disorder. Ann Clin Psychiatry. 2017;29:108-119.
  2. Schonecker M. Paroxysmal dyskinesia as the effect of megaphen [in German]. Nervenarzt. 1957;28:550-553.
  3. Gerhard T, Akincigil A, Correll CU, et al. National trends in second-generation antipsychotic augmentation for nonpsychotic depression. Clin Psychiatry. 2014;75:490-497.
  4. Rhee GT, Olfson M, Nirenberg AA. 20-year trends in the pharmacologic treatment of bipolar disorder by psychiatrists in outpatient care settings. Am J Psychiatry. 2020;177:706-715.
  5. Bhidayasiri R, Jitkritsadakul O, Friedman JH, et al. Updating the recommendations for treatment of tardive syndromes: a systematic review of new evidence and practical treatment algorithm. J Neurol Sci. 2018;389:67-75.
  6. Valbenazine [prescribing information]. San Diego, CA: Neurocrine Biosciences; 2021.
  7. Deutetrabenazine [prescribing information]. Parsippany, NJ: Teva; 2021.
  8. Aggarwal S, Serbin M, Yonan C. Indirect treatment comparison of valbenazine and deutetrabenazine efficacy and safety in tardive dyskinesia. J Comp Eff Res. 2019;8:1077-1088.
  9. Ganz ML, Chavan A, Dhanda R, et al. Cost-effectiveness of valbenazine compared with deutetrabenazine for the treatment of tardive dyskinesia. J Med Econ. 2021;24:103-113.

Your Thoughts?
I would like to hear your opinion about how you approach this issue of choosing between the 2 FDA-approved inhibitors for treating TD in your practice. In addition, I am keen to learn about your experience in using both these agents in your practice. Please recount both the adverse events your patients experience and medication adherence issues that may occur. An interesting observation to report is if TD recurred in those who stopped the VMAT2 inhibitor of their own accord. Finally, I would like to hear about the dosage you are commonly using for valbenazine and deutetrabenazine for the treatment of TD. Please share your experiences and thoughts in the comments box.

Additional resources on this topic can be found here: Evidenced-Based Approaches to Optimally Manage TD.

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