Treatment of Tardive Dyskinesia

Experts and guidelines recommend vesicular monoamine 2 transporter (VMAT2) inhibitors as the best option for treating more severe cases of tardive dyskinesia, an involuntary movement disorder caused by dopamine-blocking drugs.

The condition, which is usually irreversible, is most typically associated with sustained antipsychotic treatment. While weaning off the offending medication can resolve anywhere from 10-30% of tardive dyskinesia cases, that may not be an option for patients taking antipsychotics for schizophrenia, bipolar disorder, or psychotic depression due to the risk for disease relapse.

Most cases of tardive dyskinesia are mild, but VMAT2 inhibitors can be particularly beneficial for moderate to severe symptomology, Meghan Musselman, MD, of the Lewis Katz School of Medicine at Temple University in Philadelphia, told MedPage Today.

The FDA in 2017 approved two VMAT2 inhibitors for adults with tardive dyskinesia, once-daily valbenazine (Ingrezza) and twice-daily deutetrabenazine (Austedo), the first agents specifically indicated for the condition. While their mechanism of action is unclear, the drugs are thought to deplete dopamine and reduce tardive dyskinesia’s severity by blocking VMAT2 in nerve terminals.

“Treatment with a VMAT2 inhibitor can also be considered for patients with mild tardive dyskinesia based on factors such as patient preference, associated impairment, or effect on psychosocial functioning,” according to guidelines from the American Psychiatric Association (APA) on managing tardive dyskinesia in patients with schizophrenia.

More recently, the FDA approved a once-daily extended-release formulation of deutetrabenazine and an oral granule formulation of valbenazine (Ingrezza Sprinkle) for patients with dysphagia or difficulty swallowing.

“There are several medication options for tardive dyskinesia, with the strongest current evidence being for the use of the second-generation VMAT2 inhibitors,” said Musselman. The first-generation VMAT2 inhibitor tetrabenazine (Xenazine) — approved a decade earlier for Huntington’s disease-related chorea — has also been used off-label for tardive dyskinesia but the drug has a shorter half-life and is associated with a higher risk of side effects.

The APA recommends either deutetrabenazine or valbenazine over tetrabenazine for tardive dyskinesia “because of the greater evidence base [that] support their use.”

But other factors, including hepatic or renal function, could influence treatment decisions as well. “Tetrabenazine and deutetrabenazine are contraindicated in individuals with hepatic impairment whereas valbenazine is not recommended for use in individuals with severe renal impairment,” according to the APA guidance.

Beyond the VMAT2 inhibitors, other treatment options include ginkgo biloba and benzodiazepines such as clonazepam, said Musselman.

Joshua Kantrowitz, MD, of the Columbia University Department of Psychiatry and New York State Psychiatric Institute, both in New York City, noted that “the newer treatments, such as VMAT2 inhibitors, are more effective than the older ones.”

Supporting Data for VMAT2 Inhibition

The pivotal KINECT 3 study of valbenazine showed significantly greater reductions in the Abnormal Involuntary Movement Scale (AIMS; which ranges from 0 to 35, with higher scores indicating more severe symptoms) for patients on an 80-mg or 40-mg dose of the second-generation VMAT2 inhibitor.

From average AIMS scores of 10 at baseline, scores were reduced by a least squares (LS) mean change of 3.2 points in the 80-mg arm, 1.9 points in the 40-mg arm, and 0.1 points in the placebo arm (P<0.0001 and P=0.0021, respectively). The once-daily oral agent is approved at both dose levels.

A recent analysis of three valbenazine trials, including KINECT 3, showed no meaningful difference in treatment effect between patients taking antipsychotics at baseline compared with those who weren’t, with reductions in AIMS scores of 6.1 and 6.5, respectively. Of note, patients returned to their baseline severity after withdrawal of VMAT2 inhibitor.

Data from the AIM-TD and ARM-TD phase III trials supported the approval of deutetrabenazine. In the AIM-TD trial, the greatest reduction in AIMS score (LS mean change -3.3 points) was noted at the highest daily dose group (36 mg/day). In the flexible-dosed ARM-TD trial, AIMS scores at 12 weeks were significantly reduced with deutetrabenazine versus placebo (LS mean change of -3.0 vs -1.6 points, respectively; P=0.019).

Common adverse events (AEs) in trials of deutetrabenazine included somnolence, diarrhea, dry mouth, and fatigue; common AEs with valbenazine included somnolence in trials of tardive dyskinesia and somnolence, urticaria, rash, and insomnia in trials of chorea associated with Huntington’s disease (both drugs are also approved for this condition).

The labels for valbenazine and deutetrabenazine carry boxed warnings regarding depression and suicidal thoughts or behavior in patients with Huntington’s disease-related chorea. Other warnings and precautions shared by both drugs include risks for neuroleptic malignant syndrome, parkinsonism, and sedation/somnolence.

Both VMAT2 inhibitors also have warnings over the potential for QT prolongation, and the drugs should be avoided in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval. The two drugs should not be used simultaneously.

Musselman emphasized that the safety and effectiveness of valbenazine and deutetrabenazine have not been established in pediatric patients.

Other Options

Lower-quality evidence also lends some support to ginkgo biloba, clonazepam, and amantadine for tardive dyskinesia, and these could be options for patients who do not respond to other approaches.

According to a 2016 meta-analysis of three randomized trials in China, a 240 mg daily dose of the commonly used supplement ginkgo biloba significantly improved tardive dyskinesia symptom severity in patients with schizophrenia versus placebo.

In a 12-week randomized trial, the benzodiazepine clonazepam led to a 35% decrease in dyskinesia symptoms, though the few patients who continued on clonazepam for a few months developed a tolerance. It was effective again after a 2-week clonazepam-free period.

There has also been some mixed evidence for amantadine in tardive dyskinesia. With action as an anti-Parkinson’s and antiviral drug, amantadine was approved in 2017 under the brand name Gocovri for dyskinesia in Parkinson’s disease patients. One small 2-week crossover trial reported a nearly 22% reduction in tardive dyskinesia symptoms with the drug.

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