FDA-Approved Medications to Treat Tardive Dyskinesia

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Tardive dyskinesia (TD), a condition characterized by involuntary movements of the face, torso, extremities, and sometimes the respiratory system, is usually observed in patie​nts after long-term treatment with antipsychotic agents or other agents that block dopamine receptors.^1,2 Symptoms of TD are associated with reduced quality of life and psychosocial problems, such as social isolation and embarrassment,^3,4 and can also contribute to medication nonadherence.⁵

 PATIENT PERSPECTIVES

Patient interview conducted by Joseph P. McEvoy, MD.

Over the years, many agents have been tested in the treatment of TD, including dopamine-depleting agents, dopamine agonists, noradrenergic agonists and antagonists, GABAergic drugs, lithium, calcium channel blockers, serotonergic drugs, vitamins, branched-chain amino acids, neuropeptides, cholinergic precursors and cholinesterase inhibitors, and botulinum toxin.⁶

The American Academy of Neurology (AAN) published evidence-based guidelines regarding TD in 2013, but few treatment options had sufficient data to support or refute their use.⁷ At the time, no treatments for TD had been approved by the US Food and Drug Administration (FDA). Recently, a review of new evidence was combined with the existing guideline evidence to provide updated treatment recommendations.⁸ This activity provides an overview of treatments for patients with TD based on the AAN’s recommendations.⁸ Treatments are categorized by various levels of evidence, with Level A being a recommended, effective treatment; Level B, probably effective; and Level C, possibly effective.

Off-Label Strategies

On rare occasions, usually if TD is mild and of recent onset, reductions in the dosing of dopamine receptor blocking agents and the prescription of agents such as amantadine may result in improvement in a small percentage of patients.⁸ However, reduction in antipsychotic dosing could destabilize patients.⁹

According to the treatment guideline, amantadine and tetrabenazine are agents with Level C evidence.⁸

Amantadine. Amantadine is a noncompetitive glutamate receptor antagonist. It is postulated to work by increasing presynaptic release of dopamine and blocking presynaptic dopamine reuptake.¹⁰ Two small placebo-controlled trials reported that amantadine, when combined with neuroleptics, reduced overall AIMS scores by an average of 15% and 22%.¹¹

Tetrabenazine. Tetrabenazine is a vesicular monoamine transporter type 2 (VMAT2) inhibitor that depletes dopamine in the brain.¹² It was approved by the FDA in 2008 for the treatment of chorea in Huntington’s disease.¹³

Studies^11,14 suggest that tetrabenazine can reduce the severity of TD movements. However, the potential for adverse effects (eg, drowsiness, parkinsonism, akathisia, depression with suicidal ideation)¹¹ and lack of large, long-term treatment trials¹⁴ have prevented its wide use.

Medication-induced TD is believed to result from hypersensitive dopamine D₂ receptors,¹⁰ and the amount of dopamine in the synapse will determine how frequently these hypersensitive receptors are triggered, initiating involuntary movements. Tetrabenazine, however, is not specific for dopamine and also depletes presynaptic vesicles that collect and release serotonin, which puts patients at increased risk for depression and suicide. In addition to a black box warning for depression and suicide,¹² tetrabenazine has active metabolites that act directly as dopamine receptor blocking agents capable of causing or worsening acute extrapyramidal side effects, such as slowness and stiffness, restlessness, dystonia, and tremor. Finally, tetrabenazine is also an agent with a short half-life, requiring gradual titration up to dosing of 3 times daily.¹²

Ginkgo biloba and clonazepam may occasionally be useful for TD.¹ They have Level B evidence,⁸ but the risk-benefit profile is unfavorable.

Ginkgo biloba. A double-blind, randomized controlled trial comparing Ginkgo biloba extract and placebo in patients with schizophrenia and TD found that AIMS scores significantly decreased (P < .0001) in patients receiving ginkgo biloba versus those receiving placebo.⁷ However, clinicians must be aware that dietary supplements such as ginkgo biloba are not regulated by the FDA, which means there is no guarantee of strength, purity, or safety.¹⁵

Clonazepam. While certain benzodiazepines can cause TD, some may be beneficial in treating it.¹⁰ Clonazepam, a GABA-α agonist, has shown some effect in reducing involuntary movements in patients with TD.¹

In a 12-week study, clonazepam reduced symptoms of TD (P < .001), but for patients who continued treatment up to 9 months of open study, the drug’s effect stopped after 5–8 months.⁷ Clinicians must be aware that clonazepam is a controlled substance with potential for abuse.¹⁶

FDA-Approved TD Treatments

Two treatments for TD have been approved by the FDA and have Level A evidence: valbenazine and deutetrabenazine (AV 1).^17–21 Both agents are novel VMAT2 inhibitors and are believed to be better treatment options than off-label tetrabenazine due to tetrabenazine’s pharmacokinetic profile that requires higher, more frequent doses with greater potential for adverse effects.²² The new medications can be life changing for individuals with TD who continue to need antipsychotic treatment despite the side effects.

AV 1. Comparison of Approved Drug Treatments for Tardive Dyskinesia (0:16)

Based on Citrome 2018,¹⁷ Citrome 2017,¹⁸ and Citrome 2017,¹⁹ and package inserts for valbenazine²⁰ and deutetrabenazine.²¹ Always check the full prescribing information for updates.
^aNumber needed to treat is based on percentage of responders in Phase 3 acute studies with a 50% or greater reduction from baseline in the Abnormal Involuntary Movement Scale dyskinesia score.

 FAMILY PERSPECTIVES

Interview conducted by Joseph P. McEvoy, MD.

Valbenazine. Valbenazine is the purified parent product of one of the main tetrabenazine metabolites.²² The amino acid valine is linked by an ester bond to a metabolite of tetrabenazine.²⁰ Valbenazine is slowly metabolized, allowing for once-daily dosing.

In a phase 2 study²³ examining flexible doses of 25 to 75 mg/d of valbenazine, valbenazine proved superior to placebo in reducing AIMS dyskinesia scores (mean change of –2.6 vs –0.2, respectively; a decrease of 2 points is considered clinically meaningful²⁴). A phase 3 study²⁵ examined 40 mg/d and 80 mg/d of valbenazine versus placebo in patients with schizophrenia, schizoaffective disorder, or mood disorder (N = 205). The 80 mg/d dose produced a greater reduction in AIMS dyskinesia scores than the 40 mg/d dose (–3.2 vs –1.9) and placebo (–0.1).

An initial 40-mg/d dose and subsequent 80-mg/d dose is recommended for most patients; patients may be continued at 40 mg/d if metabolism is problematic.²⁰ The most common adverse effect of valbenazine is somnolence,²⁰ and it is also associated with fatigue, headache, gastrointestinal disturbance, and potentially prolonged QT interval. Studies have not detected differences in cardiovascular outcomes with valbenazine versus placebo.²⁶ Psychiatric stability was maintained during 1 year of treatment, with few participants experiencing suicidal ideation despite the presence of a lifetime history of suicidality in up to 40%.²⁷ Psychiatric stability was similar whether patients’ primary illness was a mood disorder or schizophrenia.²⁸

Results from a 42-week extension study²⁹ showed that reductions in mean AIMS score were maintained (AV 2). The mean changes in AIMS scores from baseline at week 48 were –3.0 with 40 mg/d and –4.8 with 80 mg/d. However, after the 4-week discontinuation and washout period, TD symptoms returned to baseline levels.^28,30 Valbenazine suppresses the abnormal movements but does not reverse the underlying damage from excessive dopamine blockade; therefore, ongoing treatment is needed.

Valbenazine is metabolized through cytochromes CYP2D6 and CYP3A4, so to avoid drug interactions, clinicians must consider other agents patients are taking that are metabolized by these cytochromes.²⁰

AV 2. Ongoing Suppression of Tardive Dyskinesia Symptoms With Valbenazine (0:29)

Adapted with permission from Factor et al.²⁹
**P < .01 vs placebo.
***P < .001 vs placebo.
^§P < .001 vs baseline.
Abbreviations: AIMS = Abnormal Involuntary Movement Scale; DBPC = double-blind, placebo-controlled period; SEM = standard error of the mean; VBZ = valbenazine; VE = valbenazine extension period.

Deutetrabenazine. The hydrogen atoms that are the initial targets in the metabolism of tetrabenazine are replaced by deuterium atoms in deutetrabenazine.¹⁹ Deuterium is a nonradioactive, stable isotope of hydrogen. Instead of having 1 proton nucleus circled by 1 electron like hydrogen does, deuterium has 1 electron and both 1 neutron and 1 proton in its nucleus, making it twice the molecular weight of hydrogen.³¹ The bonds between carbon and deuterium in deutetrabenazine are stronger than the bonds between carbon and hydrogen, which slows the metabolism of deutetrabenazine and allows reduction of peak-trough variation.³⁰ Deutetrabenazine is taken twice daily with food.

A multicenter study³² examined a flexible dose of deutetrabenazine starting at 12 mg/d (6 mg twice daily) and titrated weekly by 6 mg/d, if required, versus placebo in 117 patients with moderate-to-severe TD. Over 12 weeks, AIMS scores decreased significantly in the deutetrabenazine group versus the placebo group (−3.0 vs −1.6; P = .019), and the drug was well tolerated.

A phase 3 fixed-dose study³³ examining 12-mg, 24-mg, and 36-mg daily doses of deutetrabenazine, found that the 24-mg/d and 36-mg/d doses were superior to placebo in reducing AIMS dyskinesia scores (–3.2 in the 24 mg/d group, –3.3 in the 36 mg/d group, and –2.1 in the 12 mg/d group vs –1.4 in the placebo group).

A long-term open-label extension³⁴ of the placebo-controlled trials followed patients through week 106. Improvements from baseline in AIMS scores were maintained through endpoint (AV 3).³⁴

AV 3. Ongoing Suppression of Tardive Dyskinesia Symptoms With Deutetrabenazine (0:25)

Data from Fernandez et al.³⁴
Abbreviation: AIMS = Abnormal Involuntary Movement Scale.

The rates of side effects were similar with all 3 doses of deutetrabenazine (44%–51%) as with placebo (47%).³³ The 5 most common adverse reactions were somnolence, fatigue, insomnia, headache, and diarrhea.³³ Deutetrabenazine has a black box warning that states that it can increase the risk for depression and suicidality in patients with Huntington’s disease.²¹ During long-term treatment in patients with TD, suicidal ideation was reported in 5% of patients (5%) and suicidal behavior in < 1%; the majority of those participants had a history of depression or suicidal behavior.³⁴

Deutetrabenazine will compete with other drugs metabolized through cytochrome CYP2D6. In patients who have been tested and are known to be CYP2D6 slow metabolizers or in those with concomitant use of strong CYP2D6 inhibitors, deutetrabenazine doses greater than 18 mg twice daily are not recommended.²¹ Deutetrabenazine can slightly prolong the QT interval, so it should not be considered in patients with congenital long QT syndrome or with a history of cardiac arrhythmias. Deutetrabenazine should also be avoided or used with caution in patients with QT prolongation from other causes.²¹

Conclusion

Clinicians now have 2 FDA-approved agents to consider in the treatment of TD. Both valbenazine and deutetrabenazine are effective and tolerable agents. Neither is curative, but continuous treatment can successfully reduce TD symptoms. Clinicians should know the differences between the medications, such as administration, titration, and contraindications. Clinicians should make patients aware of any potential adverse effects. With these new options, clinicians may better help patients overcome the troubling effects of TD.

Clinical Points

• Treat patients who have TD with evidence-based agents
• Differentiate between the 2 FDA-approved agents for TD
• Follow recommended administration, titration, and monitoring of medications for TD

Abbreviations

AAN = American Academy of Neurology
AIMS = Abnormal Involuntary Movement Scale
FDA = US Food and Drug Administration
GABA = gamma-aminobutyric acid
TD = tardive dyskinesia
VMAT2 = vesicular monoamine transporter 2

© Copyright 2019 Physicians Postgraduate Press, Inc.

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