Tardive Dyskinesia: Experts Weigh in on New Treatments, Ongoing Challenges

For patients affected by tardive dyskinesia (TD), the movement disorder typically caused by dopamine-receptor blocking antipsychotic agents, recent developments could offer substantial relief. In August, deutetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, became the second medication to receive approval from the US Food and Drug Administration (FDA) for treatment of the disorder.¹ The VMAT2 inhibitor valbenazine received approval in April 2017 for the same indication.

Although the introduction of second-generation antipsychotics (SGAs) was expected to drastically reduce the incidence of TD, that ultimately was not the case.² A recent meta-analysis of 41 studies (n=11,493) found rates of 20.7% with SGAs vs 30.0% with first-generation antipsychotic treatment (95% CI, 16.6%-25.4% vs 26.4%-33.8%; Q =9.17; P =.002).³ This is of particular concern given the ever-increasing rates of SGA prescription.

Although prevention is the ideal course of action for TD management, many patients are unable to reduce exposure to the agent causing TD, and adequate treatment strategies are needed when this adverse effect occurs. One current approach is the use of another VMAT-2 inhibitor, tetrabenazine, which is approved for TD treatment in multiple countries. In the United States, the drug is approved for treatment of Huntington’s chorea and is used off-label for TD treatment.⁴

To find out how the new and pending FDA approvals may affect the state of treatment for TD, Neurology Advisor checked in with Pedro Gonzalez-Alegre, MD, PhD, associate professor at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and codirector of the Division of Movement Disorders at Penn Medicine, and Joseph M. Pierre, MD, acting chief of the Hospital Psychiatry Division at West Los Angeles VA Medical Center, and health sciences clinical professor at the David Geffen School of Medicine at the University of California, Los Angeles.

Neurology Advisor: How is TD typically treated, and what are some of the top treatment challenges?

Dr Gonzalez-Alegre: The main issue in the “treatment” of TD is prevention. It is important to use offending agents only when the potential benefit is higher than this risk. Once it appears, the first step is to determine whether symptoms are bothersome or disabling to warrant treatment. If possible, either discontinue the offending agent, although this might not improve symptoms permanently, and they will probably worsen initially, or change to a similar agent less likely to cause TD. In terms of prescription medications for TD, I have observed significant variability in treatment approaches depending on physician choice. Over the last few years, I personally found tetrabenazine to be the most efficient agent.

The main challenge is to determine when treating TD with any pharmacological agent would provide a net benefit. The underlying condition that led to the initial prescription of the offending drug is often more severe than TD, and the neurologist should never jeopardize its proper treatment trying to reduce the TD by altering the ongoing treatment or adding agents that could worsen psychiatric disease.

Dr Pierre: Although TD often goes unnoticed by patients who have it, it can be disfiguring, stigmatizing, and sometimes functionally impairing. “Treatment” begins with prevention and limiting unnecessary exposure to antipsychotic medications, which, despite the name, are used to treat a wide variety of psychiatric conditions, and these days are sometimes even used for anxiety or insomnia. However, some patients will need long-term treatment with antipsychotic medications, and the risk for TD is proportional to duration of exposure. 

Once identified, the course of TD is variable. For patients receiving first-generation antipsychotic medications who have moderate to severe TD, switching to a second-generation medication can result in symptomatic reduction and is generally advisable, although there is no guarantee antipsychotic efficacy will be preserved on switching. Clozapine can be especially effective in this regard, especially if a patient has a specific variant of TD called tardive dystonia, in which sustained muscle contractions are present. In terms of “antidotes” to TD, reliable options are limited at best. Vitamin E was initially thought to be promising as an antioxidant strategy based on small controlled trials for TD, but it was not effective in larger studies including patients with more chronic TD.

Neurology Advisor: What are your thoughts about the recently approved drugs for TD?

Dr Gonzalez-Alegre: Valbenazine and deutetrabenazine, both with the same mechanism of action as tetrabenazine, but with some differences, are welcome additions to the repertoire of agents used to treat TD. I believe that the fact that these medications are available and approved by the FDA will increase their use, thus also increasing the number of patients with TD seeking treatment and the number of physicians properly treating TD, as well as overall awareness about this condition.

Dr Pierre: To have any new medication with established efficacy in controlled trials for TD is cause for enthusiasm, although there is always room for a healthy dose of skepticism about a new drug’s magnitude of response. In the KINECT 3 trial, for example, valbenazine was superior to placebo,⁵ but the average symptom reduction was modest: 3 points on a measure that quantifies TD on a scale from 0 to 28. Most patients only improved by about 10% to 30%. That said, 40% of subjects had symptomatic reductions of 50%, and some improved by as much as 60% to 90%. This suggests valbenazine could be an impactful intervention for some patients, especially when we remember that few other options are available. 

On the risk side of things, both tetrabenazine and deutetrabenazine have FDA “black box” warnings for depression and suicidality. These possible adverse effects were therefore a concern for valbenazine in clinical trials for TD, but no such symptoms were detected in the KINECT 3 trial with valbenazine at a greater rate than placebo. 

Unfortunately, as is typically the case for new drugs, valbenazine, for example, is very expensive, estimated to cost a patient more than $60,000 per year. This may limit access for some patients.