Emerging Treatments for Tardive Syndrome

Clinical Vignette

WL, aged mid-60s, who had a 10-year history of bipolar disorder, presented with abnormal involuntary movements and facial grimacing. WL had been taking neuroleptic medications, including oral olanzapine (up to 20 mg) and lithium (900 mg/d), for the past 5 years. After 9 months, WL developed involuntary movements of the lips, tongue, and jaw, which persisted despite discontinuing olanzapine. On examination, orobuccolingual and facial dyskinesias, along with possible truncal dystonia, were observed. The Abnormal Involuntary Movement Scale (AIMS) score was 6. Tardive dyskinesia (TD) was diagnosed, and treatment with tetrabenazine (12.5 mg twice daily, titrated to 50 mg 3 times daily) was initiated. Although the tardive movements partially improved, significant parkinsonism emerged. Tetrabenazine was reduced to 25 mg 3 times daily, resulting in TD recurrence; the AIMS score increased to 12. Valbenazine (80 mg; Ingrezza; Neurocrine Biosciences, San Diego, CA) was initiated, leading to resolution of parkinsonism and partial improvement in TD.

This clinical case underscores the challenges in managing TD and the limitations of current treatment options. WL exhibited several risk factors, including advanced age, a preexisting mood disorder, and the use of lithium. The case also highlights that second-generation (atypical) antipsychotics do not eliminate the risk of TD, despite their increasing off-label use for nonpsychotic conditions. New vesicular monoamine transporter 2 (VMAT2) inhibitors offer a promising, well-tolerated symptomatic treatment for TD.

Background

Clinical recognition of TD relies on the essential features of abnormal, involuntary movements of the tongue, jaw, trunk, or extremities that develop in association with the use of medications that block postsynaptic dopamine receptors, such as first-generation or second-generation antipsychotic (SGA) medications, or other medications, such as metoclopramide for gastrointestinal disorders.¹ Abnormal orofacial movements, often referred to as orobuccolingual dyskinesia, are the most obvious manifestation, leading to a diagnosis of TD; however, approximately 50% of individuals have limb involvement, and up to 25% have axial dyskinesia of the neck, shoulders, or trunk, resulting in a proposed nosology of tardive syndrome (TS) to refer to the spectrum of all persistent hyperkinetic, hypokinetic, and sensory phenomenologies.²

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR), TD diagnosis requires persistence of the movement disorder for at least 1 month and its association with the use of a dopamine receptor blocking agent (DRBA) of at least 3 months (or 1 month in individuals older than 60 y), whereas TS refers to other types of movement problems, such as dystonia or akathisia, that are distinguished by late emergence in the course of treatment and potential persistence, even with discontinuation of DRBAs.¹ In clinical practice, these 2 terms have been used interchangeably, but TS is more of an umbrella term to include a range of tardive movement disorders as well as the most recognized syndrome—orobuccolingual dyskinesia—and is referred within this article as such. TD is used in this article to denote classic orobuccolingual dyskinesia or when it is specifically mentioned in the cited literature.

SGAs, although commonly believed to provide a greater safety margin, do not offer a significantly higher level of safety or lower incidence of the syndrome.^3,4 Different SGAs have been associated with varying degrees of drug-induced movement disorders, with clozapine having the lowest risk and lurasidone and risperidone having the highest risk.⁵ Prevalence studies highlight the ongoing clinical significance of TS because of the increasing use of SGAs, particularly for off-label conditions such as bipolar disease, depression, and insomnia.⁶ Recent data have revealed a significant rise in antipsychotic prescribing in the United States, with a threefold increase overall and a substantial 10-fold surge among children, indicating that at least 5 million people are exposed to antipsychotics annually.⁷

TS can affect individuals with or without psychiatric conditions, leading to adverse health care outcomes, reduced quality of life, and higher mortality rates when compared with individuals using antipsychotics without TS.⁸ Considering these factors, it is essential to explore emerging treatments for TS to address the challenges associated with this condition and enhance outcomes.

Pathophysiology

Understanding of the pathophysiology of TS remains incomplete, with several theories proposed in an attempt to explain the underlying mechanisms. A commonly acknowledged explanation involves the increased sensitivity of dopamine D2 and potentially D3 receptors after prolonged blocking by DRBAs. This hypersensitivity of D2 receptors results in an overactive indirect pathway that typically suppresses movement, ultimately contributing to hyperkinesias observed in TS.⁹ Evidence supporting this theory includes observations that abrupt discontinuation of DRBAs can worsen symptoms, whereas drugs with more robust dopamine blockade or depletion can alleviate the associated movements. Studies in rodents have demonstrated receptor hypersensitivity, but human studies have produced mixed results, and the long-term effects of DRBAs on receptor sensitivity are not consistently supported.

Another hypothesis suggests that structural changes may occur in the synapse or the presynaptic dopamine-secreting neurons as a result of direct toxic effects or oxidative stress induced by DRBAs. These agents can inhibit the electron transport chain, increasing dopamine turnover and generating harmful reactive oxygen species, causing neuronal damage. Animal models have shown evidence of increased membrane lipid peroxidation and glutamate transmission as well as reduced antioxidant enzyme activity, supporting this hypothesis.¹⁰

Genetic predisposition also is believed to be a contributing factor, potentially explaining why certain individuals are more susceptible to developing TS. Several human genetics studies have identified associations between TS and variations in genes encoding dopamine, serotonin, or other neurotransmitter receptors, which may influence both the risk of developing the disorder and its specific characteristics and severity.¹¹

Clinical Assessment

The Figure presents an algorithm that provides guidance for TS evaluation in clinical settings. When evaluating individuals with suspected TS, it is imperative to consider psychiatric history, particularly chronic psychiatric disorders such as schizophrenia or bipolar disease, along with a reliable medication history, including recent dose adjustments, history of alcohol or substance abuse, and the use of lithium or antiparkinsonian agents.⁶ However, individuals may not always be aware of their movements, especially in certain TS, like choreoathetosis and stereotypy.

TS previously was frequently overlooked, but its identification has improved over time. AIMS is the standard tool for evaluation; however, it focuses on choreoathetoid movements and stereotypies, whereas akathisia is assessed separately.^12,13 The Schooler–Kane criteria typically are used for diagnosing TS based on AIMS score of at least 2 in ≥2 body regions or a score of 3 or 4 in ≥1 body region and meeting the DSM-5-TR criteria for onset and duration.¹⁴

Following a diagnosis of TS, a systematic evaluation using AIMS is recommended to assess the severity, distribution, and phenomenology of the movements, as well as their functional effects on the individual.^12,13 Management of TS involves modifying the antipsychotic medication regimen (eg, dose reduction, switching to another antipsychotic, discontinuation of antipsychotic medication), especially if the current drug is being used off-label.¹⁵ For individuals with psychotic disorders requiring long-term antipsychotic therapy, the decision to reduce the dose must be balanced with the risk of exacerbating psychiatric symptoms or inducing withdrawal-emergent dyskinesia. In such cases, switching to SGAs with lower D2 receptor affinity, such as clozapine or quetiapine,¹⁶ may be considered, although conflicting evidence exists to support this approach.¹⁵

Anticholinergics are frequently prescribed to manage antipsychotic-induced parkinsonism and dystonia, but their use in TD is uncertain and could exacerbate the condition. Therefore, if anticholinergic agents are coprescribed in a person with TD, it is advisable to consider reducing or discontinuing them.⁷ When TS symptoms persist despite optimization of antipsychotic treatment, specific suppressive treatments should be considered.

Pharmacologic Interventions

Before 2017, no medications had received Food and Drug Administration (FDA) approval for the treatment of TS. However, numerous off-label agents were attempted, such as bromocriptine, acetazolamide, baclofen, vitamin E, vitamin B6, thiamine, selegiline, melatonin, nifedipine, levetiracetam, methyldopa, reserpine, and buspirone.¹⁵ In 2013, the American Academy of Neurology released treatment guidelines for TS, highlighting only 2 drugs with level B evidence (clonazepam and Gingko biloba) and 2 with level C evidence (amantadine and tetrabenazine).¹⁵

Clonazepam, a benzodiazepine with indirect GABA agonist activity, showed some promise for TS treatment, but its use was limited because of concerns regarding acute and long-term side effects, including sedation, cognitive decline, tolerance, and dependence.¹⁷

Gingko biloba, acting as an antioxidant, demonstrated potential efficacy in reducing symptoms, possibly through its effects on brain-derived neurotrophic factor signaling.¹⁸

Amantadine, a blocker of N-methyl-D-aspartate glutamate receptors, had a modest effect in symptom reduction,¹⁹ but the evidence supporting its use was scant, making it a consideration only when other established treatments were not viable.¹⁵

Tetrabenazine, a selective VMAT2 inhibitor, is a prototype drug that works by reducing presynaptic storage and release of dopamine, norepinephrine, and serotonin in the neuron, resulting in decreased activation of postsynaptic dopamine receptors in the nigrostriatal pathway, and, consequently, reduced dyskinetic movements.²⁰ Several studies have demonstrated its effectiveness in treating TS, but tetrabenazine is hindered by its short half-life, necessitating 3 times daily dosing, leading to fluctuating plasma levels and potentially causing side effects such as sedation, parkinsonism, akathisia, and depression.²¹ Tetrabenazine’s metabolism is also influenced by CYP 2D6, and for doses greater than 50 mg/d, genotyping is recommended.²² Tetrabenazine carries an FDA black box warning for suicidality in individuals with Huntington disease.²³

FDA-Approved Medications for Tardive Dyskinesia

The American Academy of Neurology guideline recently was updated to incorporate 2 FDA-approved VMAT2 inhibitors: valbenazine and deutetrabenazine (Austedo XR; Teva Neuroscience, Overland Park, KS) (Table).²⁴ These agents marked a significant milestone as they had undergone multicenter, randomized, double-blind clinical trials; were the first to be supported by level A evidence; and were specifically approved for the treatment of TD in the United States.²⁵

Valbenazine is a prodrug of the most active isomer of tetrabenazine, metabolized into dihydrotetrabenazine, a potent selective inhibitor of VMAT2.²⁶ Designed to minimize peak plasma concentrations and reduce intersubject and intrasubject variability, with a half-life of approximately 20 hours, valbenazine enables convenient once-daily dosing.²⁷ Optimal efficacy is achieved with the 80 mg/d dose, and significant improvement is observed after 1 week on 40 mg/d. Two randomized trials demonstrated significant improvement in AIMS severity scores and clinical global impression with valbenazine compared with placebo, supporting its efficacy and tolerability for TD treatment.^28,29 Long-term studies demonstrated sustained benefits over 42 weeks and 48 weeks without notable worsening of psychiatric disorders.^30,31

Deutetrabenazine is an isotopic isomer of tetrabenazine, containing deuterium, which modifies drug metabolism, resulting in a prolonged half-life and enabling twice-daily dosing with reduced peak concentrations.³² Unlike valbenazine, with a fixed target dose of 80 mg/d, the deutetrabenazine dose is individualized for each person based on TD reduction and tolerability. The recommended initial dose for TD treatment is 6 mg twice daily, with gradual weekly increments of 6 mg/d, up to a maximum daily dosage of 48 mg.³² Deutetrabenazine studies have demonstrated significant improvements in AIMS severity scores compared with placebo, without notable worsening of parkinsonism or akathisia.^33,34 Long-term efficacy and tolerability have been sustained for up to 80 weeks.³⁵

Overall, valbenazine and deutetrabenazine present promising emerging therapeutic options for TS, with a favorable benefit-risk profile that warrants their consideration as first-line treatments.²⁴ Their notably longer serum half-lives compared with tetrabenazine result in a more sustained pharmacokinetic profile, contributing to reduced side effects, thereby avoiding issues such as depression and parkinsonism.^27,36 Valbenazine offers the advantage of straightforward titration with once-a-day dosing, whereas deutetrabenazine allows for more precise titration with smaller increments. Valbenazine also has a single metabolite, potentially resulting in fewer off-target effects and reduced side effects compared with deutetrabenazine and tetrabenazine. Valbenazine can be used safely in individuals with mild hepatic impairment or renal impairment, whereas deutetrabenazine and tetrabenazine are contraindicated in such cases.^27,32,37,38

Genetic testing is not mandatory, but dose adjustments are recommended when coadministering CYP 2D6 or CYP 3A4 modulators.^27,32 Careful monitoring is essential, particularly for poor metabolizers, because of the potential for QTc prolongation and CYP2D6 metabolism. Although variability in response to VMAT2 inhibitors based on phenomenology has yet to be studied, earlier trials have shown improvements in tardive dystonia and tardive akathisia with these medications.^30,31,35 If one of these VMAT2 inhibitors is ineffective or intolerable, a second drug should be tried; however, additional comparative efficacy research is needed.

Personalized Treatment Approaches and Future Perspectives for TS

Formulating individualized treatment plans for TS is crucial, considering unique clinical features, medical history, and the varying response and tolerance to available medication regimens. VMAT2 inhibitors (ie, valbenazine and deutetrabenazine) have shown promise as effective symptomatic treatments for TS. However, not all individuals may respond to or tolerate these drugs. In such cases, other pharmacologic agents can be considered based on a risk-benefit review.

The use of botulinum toxin varies based on the specific phenotype but may serve as a first-line treatment for tardive dystonia, especially craniocervical dystonia, or as part of treatment for classic TD with orobuccolingual involvement. If medical therapies prove ineffective, surgical therapy, particularly deep brain stimulation targeting the globus pallidus internus, may be considered as an alternative option.

Research should prioritize advancing our comprehension of the underlying mechanisms of TS to promote the development of treatments that specifically target these mechanisms, not only to offer symptomatic improvement, but also to explore the potential for reversal and preventive approaches. Perspectives in TS management involve the identification of biomarkers for early detection and monitoring, advancements in genetic and pharmacogenetic profiling for tailored interventions, and integrating novel nonpharmacologic strategies, such as transcranial magnetic stimulation.

Conclusion

TS significantly affects people’s quality of life and remains a substantial public health concern. SGAs do not significantly mitigate the risk and their increasing off-label use for nonpsychotic indications may elevate prevalence; therefore, proactive measures are vital for prevention. Clinicians should adhere to best practice guidance in antipsychotic prescription, including limited use for specific indications, use of the minimum effective dose, and minimization of treatment duration. Although the FDA-approved VMAT-2 inhibitors valbenazine and deutetrabenazine have proven effective and safe as symptomatic treatments, conducting further studies to explore potential mechanisms for disease reversal remains crucial. A personalized approach that considers individual risk factors, clinical manifestations, and treatment responses will offer more effective and well-tolerated management strategies for this challenging movement disorder.