VMAT2 Inhibitor Choice for TD

Choosing the Right VMAT2 Inhibitor for TD

Released: November 19, 2021

Expiration: November 18, 2022

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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

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What have you most often prescribed for TD in the past year?

A. Deutetrabenazine
B. Valbenazine
C. Other

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