Treatment of Tardive Dyskinesia: A General Overview with Focus on the Vesicular Monoamine Transporter 2 Inhibitors

Abstract

Tardive dyskinesia (TD) encompasses the spectrum of iatrogenic hyperkinetic movement disorders following exposure to dopamine receptor-blocking agents (DRBAs). Despite the advent of atypical or second- and third-generation antipsychotics with a presumably lower risk of complications, TD remains a persistent and challenging problem. Prevention is the first step in mitigating the risk of TD, but early recognition, gradual withdrawal of offending medications, and appropriate treatment are also critical. As TD is often a persistent and troublesome disorder, specific antidyskinetic therapies are often needed for symptomatic relief. The vesicular monoamine transporter 2 (VMAT2) inhibitors, which include tetrabenazine, deutetrabenazine, and valbenazine, are considered the treatment of choice for most patients with TD. Deutetrabenazine-a deuterated version of tetrabenazine-and valbenazine, the purified parent product of one of the main tetrabenazine metabolites, are novel VMAT2 inhibitors and the only drugs to receive approval from the US FDA for the treatment of TD. VMAT2 inhibitors deplete presynaptic dopamine and reduce involuntary movements in many hyperkinetic movement disorders, particularly TD, Huntington disease, and Tourette syndrome. The active metabolites of the VMAT2 inhibitors have high affinity for VMAT2 and minimal off-target binding. Compared with tetrabenazine, deutetrabenazine and valbenazine have pharmacokinetic advantages that translate into less frequent dosing and better tolerability. However, no head-to-head studies have compared the various VMAT2 inhibitors. One of the major advantages of VMAT2 inhibitors over DRBAs, which are still being used by some clinicians in the treatment of some hyperkinetic disorders, including TD, is that they are not associated with the development of TD. We also briefly discuss other treatment options for TD, including amantadine, clonazepam, Gingko biloba, zolpidem, botulinum toxin, and deep brain stimulation. Treatment of TD and other drug-induced movement disorders must be individualized and based on the severity, phenomenology, potential side effects, and other factors discussed in this review.

Selecting dopamine depleters for hyperkinetic movement disorders: how do we choose?

“…Furthermore, in a case of severe concomitant neuropsychiatric symptoms with the possibility of considerable aggravation by TBZ, DTBZ may come into account as a first choice. Regarding TD, a realworld study published in 2019 and a review article focused on TD highlighted that all three VMAT2 inhibitors are effective and safe for treatment of these abnormal involuntary movements [20,21], but only DTBZ and VBZ have FDA approval. There is only one indirect comparison of these two agents available which delineated VBZ as statistically more effective than DTBZ in AIMS score improvements, whereas there was no relevant difference in safety parameters [22].…”

Synthesis of Tetrabenazine and Its Derivatives, Pursuing Efficiency and Selectivity

“…To release dopamine from the presynaptic neuron to the synaptic cleft, active transport of dopamine into the vesicle in neuronal cells occurs [1]. Vesicular monoamine transporter type 2 (VMAT2) is responsible for packaging dopamine in the neuronal vesicle by importing dopamine via an ATP-dependent mechanism [2]. Due to the importance of VMAT2 in controlling the dopamine levels found in the human body, numerous approaches to controlling VMAT2 have been studied toward the treatment of related diseases, such as Parkinson's disease (PD) [3], Huntington's disease (HD) [4], and schizophrenia [5].…”

“…importing dopamine via an ATP-dependent mechanism [2]. Due to the importance of VMAT2 in controlling the dopamine levels found in the human body, numerous approaches to controlling VMAT2 have been studied toward the treatment of related diseases, such as Parkinson's disease (PD) [3], Huntington's disease (HD) [4], and schizophrenia [5].…”

Comparing pharmacologic mechanism of action for the vesicular monoamine transporter 2 (VMAT2) inhibitors valbenazine and deutetrabenazine in treating tardive dyskinesia: does one have advantages over the other?

“…The introduction of 2 different treatments has revitalized interest in tardive dyskinesia (TD), especially how to recognize and manage it. [1][2][3][4][5][6][7][8][9][10][11][12] Both therapeutic options-valbenazine and deutetrabenazine-are based on tetrabenazine pharmacology. By blocking the vesicular monoamine transporter type 2 (VMAT2) in their own unique ways, both improve the involuntary movements of TD due to reducing dopamine availability at hypothetically supersensitive D2 dopamine receptors in the motor striatum.…”

“…Comparisons have already been made in several review articles by looking at how each drug performs against placebo in separate clinical trials. [5][6][7][8][9][10][11][12] The differences in safety and efficacy of the two new treatments studied in those trials have been extensively discussed elsewhere, [5][6][7][8][9][10][11][12] with the two tardive dyskinesia treatments showing more similarities than differences. Here we look at these two agents in another way; namely, by contrasting their individual pharmacologic mechanisms of action.…”