Vesicular Monoamine Transporter 2 Inhibitors for Treating Adult Tardive Dyskinesia

Tardive dyskinesia (TD), which affects more than 573,000 adults in the United States, is a heterogeneous disorder of involuntary movements that is often persistent and is characterized by choreiform and athetoid movements of the face, trunk, mouth, and extremities.1 Postural abnormalities, rocking, and rotary pelvic movements have also been recorded.2

Causes of TD

Typically, TD is caused by prolonged exposure to antipsychotics or dopamine-receptor blockers used to treat schizophrenia and other affective disorders. Antiemetics, calcium channel blockers, lithium, antitussives, and antidepressants have also been associated with inducing TD.2-5
A rapid increase in antipsychotic prescriptions over the past 2 decades, owing to off-label and adjunctive uses in treating depression, has contributed to a concurrent increase in the prevalence of TD (Figure 1).

Although the global prevalence of TD is unknown, a recent meta-analysis estimates it as 25.3% of antipsychotic users.6 Second-generation antipsychotic (SGA) medications, owing to their unique mechanisms in dopamine antagonism and selective agonism, have been purported to be associated with a reduced risk of TD compared with first-generation antipsychotics (FGAs)7; however, some studies have shown no relative difference in incidence of TD between the 2 classes of medication.8,9
The morbidity associated with TD symptoms can vary widely from one patient to the next, but the persistent and pronounced nature of these abnormal movements significantly reduces quality of life and exacerbates the sense of alienation caused by mental illness. Additionally, patients who develop TD have a high risk of nonadherence to treatment, thus aggravating the morbidity of underlying disease.
Early diagnosis and treatment are critical for reducing the physical, mental, and social deficits associated with TD.10 To that end, this article summarizes current understanding of TD treatment.

Tapering Causative Medications

The first line of therapy in the management of TD is cessation of the causative medication.11 However, withdrawal of medication is viable only among patients with well-controlled psychiatric illness. In patients for whom medication cannot be withdrawn, switching to an SGA or another FGA with a lower risk of TD is recommended.10
Despite a lack of controlled studies, empirical evidence supports switching to clozapine to treat existing TD, which is the recommendation of the American Psychiatric Association.12 In the past, increasing the dosage of a patient’s antipsychotic was recommended to mask symptoms of TD; however, because these effects are only short-lived and can lead to worsening parkinsonism, this strategy is no longer recommended.13
Only 2% of patients with TD benefit from medication withdrawal. Additionally, 33% to 55% of patients experience worsening of TD symptoms upon cessation of an antipsychotic.14-16 Taken together with the fact that withdrawing from an antipsychotic is most effective when implemented immediately after symptoms appear, these findings have led to an understanding that there is a limited period after TD appears during which the disorder is reversible.17

Vesicular Monoamine Transporter 2 Inhibitors

Although the pathophysiology of TD has not been fully elucidated, postsynaptic dopamine hypersensitivity resulting from chronic dopamine receptor inhibition is believed to play a role. This led to investigation of drug molecules that could be utilized to regulate signaling without binding to dopamine receptors.18 Vesicular monoamine transporter 2 (VMAT2) inhibitors block vesicular monoamine transporters that deliver dopamine and other monoamines into presynaptic vesicles. Subsequently, they facilitate depletion of dopamine levels without risk of hypersensitivity.10
Three VMAT2 inhibitors have demonstrated the most promising evidence in the management of TD.
Tetrabenazine (Xenazine®; Valeant Pharmaceuticals), developed as an antipsychotic, is used off-label for the treatment of TD. In open-label observational studies, tetrabenazine (TBZ) demonstrated moderate efficacy in treating adults with TD. However, owing to the short half-life of the compound, TBZ needs to be administered at high doses at least 3 times a day. Furthermore, TBZ has been associated with high risk of adverse events, including anxiety, depression, suicidal ideation, sedation, akathisia, and parkinsonism.19
Deutetrabenazine (Austedo®; Teva), the deuterated form of TBZ, was developed to address the reduced persistence and efficacy of TBZ. Replacement of hydrogen atoms with the deuterium isotope delays metabolic degradation, thus prolonging half-life and stability. As a result, deutetrabenazine (DTBZ) demonstrates higher efficacy than TBZ at much lower dosages.20
DTBZ (at 12 mg/d, 24 mg/d, 36 mg/d, and 48 mg/d) has demonstrated a significant decrease in symptoms in 2 double-blind, placebo-controlled phase 3 trials. Additionally, DTBZ was well tolerated with a minimal adverse-effect profile (somnolence, insomnia, akathisia, depression).21
DTBZ was approved for use in TD by the US Food and Drug Administration (FDA) in 2017.22 The recommended starting dosage is 6 mg twice a day; however, open-label extension studies have confirmed a favorable safety profile of DTBZ both during titration and maintenance as high as 48 mg/d.23-25 DTBZ is contraindicated in patients with depression, suicidal ideation, hepatic dysfunction, and cardiovascular disorders, as well as in patients who are breast feeding, pregnant, or taking a monoamine oxidase inhibitor or a cytochrome P450 3A4 or 2D6 inhibitor.20
Valbenazine (Ingrezza®; Neurocrine Biosciences), a purified isoform of TBZ, was approved for use in the treatment of TD by the FDA in 2017. Because valbenazine is metabolized slowly, it offers the advantage of high efficacy with single daily dosing. In 3 randomized, double-blind, placebo-controlled studies, valbenazine demonstrated tolerance with dosage as high as 75 mg/d, with a significant decrease in scores on the Abnormal Involuntary Movement Scale (AIMS). In subsequent extension studies, only a minimal incidence of adverse events — dry mouth, akathisia, fatigue, and headache — was noted following 48 weeks of valbenazine use.26
Interestingly, after 48 weeks of valbenazine use, older patients experienced greater improvement in symptoms than younger patients.27 However, it was noted that, on average, there was minor worsening in symptoms of depression. As a result, it is advised that patients taking valbenazine continue to be monitored closely. Despite a significant percentage of the clinical trial cohort having a history of a cardiovascular disorder, valbenazine did not provoke adverse events. A small increase in the rate of prolonged QT interval (delayed ventricular repolarization) was detected, however, which has yet to be thoroughly examined.28
Compared with DTBZ, valbenazine demonstrates fewer adverse effects, higher efficacy with a single dosing regimen, and cost efficiency.29 The recommended starting dosage is 40 mg/d; like DTBZ, it is advised that valbenazine not be taken concomitantly with a monoamine oxidase inhibitor or cytochrome P450 3A4 or 2D6 inhibitor. The safety of valbenazine in pregnant or lactating women and pediatric patients has not been sufficiently examined.29

Other Medications for the Treatment of TD

In addition to VMAT2 inhibitors, several classes of medications have demonstrated moderate to low efficacy for alleviating symptoms of TD:

  • Amantadine (Gocovri®; Adamas Pharmaceuticals), approved for use in Parkinson disease, has demonstrated improvement in AIMS scores in some patients with TD.30
  • Anticholinergics have also demonstrated a reduction in TD morbidity; however, evidence for this is inconsistent.13 Furthermore, in a recent trial, the anticholinergic varenicline (Chantix®; Champix®; Pfizer), an agonist for nicotinic acetylcholine receptors, failed to improve AIMS scores in patients with TD.17
  • Gamma aminobutyric acid agonists. A meta-analysis failed to show any improvement in TD symptoms with gamma aminobutyric acid (GABA) agonists such as clonazepam (Klonopin®; Genentech). Furthermore, the use of GABA agonists in patients with TD is associated with a risk of mental deterioration, sedation, and ataxia.31
  • Chemodenervation using botulinum toxin has been successful in patients with TD and severe orofacial dystonia and tongue protrusions.32
  • Antioxidants, Ginkgo biloba, vitamin E,and vitamin B6 have been put forward for the treatment of TD; however, there is no published evidence to validate their use.13

Deep Brain Stimulation for TD

Deep brain stimulation (DBS) has been successfully utilized for the treatment of several movement disorders. In patients with TD, pallidal DBS has been shown to reduce the morbidity of symptoms.33 More recently, bilateral pallidal simulation decreased TD symptoms and AIMS scores by 50% at 6 months, and these effects were maintained after 12 months, 6 years, and 11 years.34 However, owing to the risk of adverse effects — including infection, exacerbation of psychiatric symptoms, gait disorder, and perioperative complications — DBS is recommended for use only in patients with severe, debilitating TD.13

Choosing the Right Treatment Pathway

Once a diagnosis of TD has been made, treatment is a highly individualized process that depends on consideration of a range of pre-existing conditions, the severity of symptoms, and additional risk factors. Typically, psychiatrists and neurologists work together to provide multidisciplinary care to balance the risk of TD and management of underlying psychiatric illness.10
Combining the need for individualization with other accumulated evidence, Figure 2 presents clinicians with a treatment decision guide for TD. 

The regulatory approvals of DTBZ and valbenazine present a unique opportunity in the treatment of TD. However, as a first line of defense, clinicians must continue to judiciously limit the use of antipsychotics. Additionally, because early diagnosis of TD can significantly improve prognosis, patients taking an antipsychotic must be continuously monitored for symptoms of TD.
Throughout the treatment pathway, clinicians are advised to consistently use the AIMS scale to assess the impact of treatment.35 Furthermore, effective management of TD requires the informed consent and participation of the patient in the treatment strategy. To that end, clinicians should seek to assess patient preferences and quality of life when designing each step of the treatment pathway.


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                                                                                                                                       Reviewed August 2021