Recent Advances in the Pharmacology of Tardive Dyskinesia

Abstract

Tardive dyskinesia (TD) is a syndrome of abnormal involuntary movements that follows treatment with dopamine D2-receptor antagonists. Recent approval of vesicular monoamine transporter-2 (VMAT2) inhibitors offers hope for reducing the impact of TD. Although these drugs represent a significant advance in patient care and a practical step forward in providing relief for patients with TD, understanding of the pharmacology of TD that could inform future research to prevent and reverse TD remains incomplete. This review surveys evidence for the effectiveness of VMAT2 inhibitors and other agents in the context of theories of pathogenesis of TD. In patients for whom VMAT2 inhibitors are ineffective or intolerable, as well as for extending therapeutic options and insights regarding underlying mechanisms, a review of clinical trial results examined as experimental tests of etiologic hypotheses is worthwhile. There are still compelling reasons for further investigations of the pharmacology of TD, which could generate alternative preventive and potentially curative treatments. Finally, benefits from novel drugs are best realized within an overall treatment strategy addressing the condition and needs of individual patients.

A new era in the diagnosis and treatment of tardive dyskinesia

“…Numerous and mostly flawed past clinical trials of agents engaging diverse pharmacological targets yielded inconclusive or negative results. 141,143,[157][158][159] In contrast, recent trials have provided robust evidence on the efficacy and tolerability of valbenazine and deutetrabenazine (Table 4). Like tetrabenazine, these drugs act to deplete dopamine and thereby reduce the severity of TD by inhibiting VMAT2 in nerve terminals, which ordinarily protects dopamine from the metabolic breakdown by transporting monoamines into protective vesicles.…”

Treatable Hyperkinetic Movement Disorders Not to Be Missed

“…Switching to a drug with a lower affinity to D2 receptors, such as clozapine, is recommended in case pursuing neuroleptic treatment is mandatory (140). Antipsychotic reduction or switching are likely to have a positive clinical effect on reduction or reversibility of tardive dyskinesia, although not always statistically confirmed by some studies (141)(142)(143)(144). Neither prophylaxis with anticholinergics nor symptomatic treatment with GABA agonists are recommended due to lack of evidence supporting their use (143,145,146).…”

“…Antipsychotic reduction or switching are likely to have a positive clinical effect on reduction or reversibility of tardive dyskinesia, although not always statistically confirmed by some studies (141)(142)(143)(144). Neither prophylaxis with anticholinergics nor symptomatic treatment with GABA agonists are recommended due to lack of evidence supporting their use (143,145,146). Treatments that can be added are dopamine depleting agents, VMAT2 inhibitors such as (deu) tetrabenazine or valbenazine in case of tardive syndromes, botulinum toxin for focal dystonia, and Gpi-DBS can be discussed in case of refractory disabling tardive dyskinesia (143,147,148).…”

“…Neither prophylaxis with anticholinergics nor symptomatic treatment with GABA agonists are recommended due to lack of evidence supporting their use ( 143 , 145 , 146 ). Treatments that can be added are dopamine depleting agents, VMAT2 inhibitors such as (deu) tetrabenazine or valbenazine in case of tardive syndromes, botulinum toxin for focal dystonia, and Gpi-DBS can be discussed in case of refractory disabling tardive dyskinesia ( 143 , 147 , 148 ). A seminal prospective study demonstrated a sustained 50% improvement in patients who had underwent GPi-DBS for tardive dystonia and dyskinesia ( 147 ).…”

Pharmacokinetics, safety and tolerability of valbenazine in Korean CYP2D6 normal and intermediate metabolizers

“…Valbenazine is a selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of tardive dyskinesia 8 . As tardive dyskinesia can be caused by postsynaptic super‐sensitivity of dopamine D2‐receptors, an agent that can block or deplete dopamine can be used as a medical treatment for tardive dyskinesia 9 . VMAT2 is the integral membrane protein that transports monoamines from the cellular cytosol to synaptic vesicles and plays an important role in the release of dopamine 10 .…”