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Untitled, Victor Babeş (1911)
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This week, valbenazine became the first-ever drug approved by the Food and Drug Administration (FDA) for the treatment of tardive dyskinesia. Today, Psych Unseen answers some questions about the significance of this news.

What is tardive dyskinesia?

“Tardive dyskinesia” (TD) is a medical term that literally means “late-onset abnormal movements” and is specifically used to describe an involuntary movement disorder caused by cumulative exposure to antipsychotic medications and other related drugs (including some antidepressants and medications used to treat nausea like prochlorperazine (Compazine®) or metoclopramide (Reglan®)). Tardive dyskinesia is a risk for anyone taking these types of medications, occurring at a rate of up to 1-5% per year of exposure.

Although the term TD is sometimes used generically for any medical-related abnormal movements, it is more correctly or precisely applied to “choreiform” movements that are defined by their short amplitude, irregularity, and jerkiness. These movements typically occur in the lower face with lip smacking, tongue protrusion, or side-to-side movements of the jaw and as well as in the hands and feet with so-called “piano playing” or “guitar strumming” movements of the fingers.

In popular culture, Michael J. Fox portrayed a character with TD in the TV show The Good Wife. Since the movements of TD can resemble the movements associated with medications taken for Parkinson’s disease, scripting the disorder into his character gave the show a way to account for the actor’s own movements.

At best, TD is disfiguring and stigmatizing; at worst it can impair motor function, speech, and even breathing (though it's not generally life-threatening). Tardive dyskinesia is best managed through prevention by minimizing unnecessary exposure to antipsychotic medications and by prescribing the newer “second-generation” antipsychotic medications that appear to have a lower risk compared to older drugs. However, once it occurs, it's often irreversible and there has never been a medication specifically approved by the FDA for the treatment of TD.

What is valbenazine?

Valbenazine is a “vesicular monoamine transporter 2 (VMAT2) inhibitor” that acts by decreasing the release of "presynaptic" dopamine so that overall there's less dopamine present in the space between the ends of neurons where they communicate with each other. Since TD has been conceptualized as being caused by long-term exposure to antipsychotics that block dopamine transmission between neurons resulting in a state of dopamine “supersensitivity,” it was thought that valbenazine’s effects on dopamine release could lessen the effects of that supersensitivity. In addition, it's possible that by decreasing release of dopamine, valbenazine could help with psychotic symptoms, which are more likely to occur when there's “too much” dopamine between neurons, such as when someone uses cocaine or methamphetamines, or when patients with Parkinson’s disease take dopamine as a medication in the form of L-dopa.

Valbenazine isn’t the first-ever VMAT2 inhibitor to be approved by the FDA, it’s just the first-ever VMAT2 inhibitor approved for the treatment of TD. Tetrabenazine (trade name Xenazine®) and deutetrabenazine (trade name Austedo®) are two other VMAT2 inhibitors already approved by the FDA for Huntington’s disease (a genetic disorder that, like TD, also includes choreiform movements). It's anticipated that deutetrabenazine will also be approved for the treatment of TD later this year. Meanwhile, while valbenazine has just been approved by the FDA, it hasn't yet been released by the company that manufactures it. It's anticipated that Neurocrine Biosciences will release valbenazine in the near future under the trade name Igrezza®.

What does the evidence say about valbenazine as a treatment for tardive dyskinesia?

The main study that resulted in FDA approval of valbenazine was recently published online in the American Journal of Psychiatry.2 The study was a 6-week, double-blind, placebo-controlled trial with two different doses of valbenazine (40 mg/day and 80 mg/day) added to existing treatment with other psychiatric medications. The study subjects were comprised of 225 adults with mental illness but stable psychiatric symptoms and a diagnosis of TD. The main outcome of the study was the total score on the Abnormal Involuntary Movement Scale (AIMS), used to quantify the severity of TD.

At the end of 6 weeks, subjects treated with valbenazine 80 mg/day did significantly better than those treated with placebo in terms of improvement in their AIMS score. On average, subjects on the higher dose of valbenazine improved by about 3 points on the AIMS and about 40% of those subjects had at least a 50% reduction in AIMS score.

Side effects were mild, with sedation and dry mouth the only adverse events occurring in more than 5% of the subjects who received valbenazine. Suicidal ideation was reported in a small minority of treated subjects, but it was less frequent than it was for patients treated with placebo.

Is the hype surrounding valbenazine deserved?

In a clinical trial, “statistical significance” is the standard benchmark to determine whether a new treatment is better than no medication (placebo). In this study, statistical significance was achieved for the higher dose of valbenazine, but the average improvement in TD as measured by the AIMS was modest at only 3 points, leaving open the question of whether that degree of change is “clinical significant” or likely to have a meaningful impact on symptoms of TD.

The authors of the study comment on this question in their discussion, but clinical significance can only really be answered at the level of an individual, not based on study averages. For example, the average AIMS score for study subjects was about 10. With a total score on the AIMS that can range from 0 to 28 in severity, an average improvement of 3 points might have questionable clinical significance and indeed, most patients on the highest dose of valbenazine only improved by 10-30% on the AIMS. But those averages don’t take into account individual responses—as mentioned, 40% of those treated at the higher dose of valbenazine improved by 50% and some improved by as much as 60-90%. That kind of response is much more likely to be clinically significant.

Tetrabenazine and deutetrabenazine, the other VMAT2 inhibitors approved by the FDA, carry “black-box warnings” for suicidality and depression among patients with Huntington's disease, so the effect of valbenazine on psychiatric symptoms was closely monitored in this study. As noted already, suicidality did not occur more frequently with subjects on valbenazine compared to placebo and no patients reported depression as a side effect. Scores that measured changes in mood and psychotic symptoms did not worsen with active treatment. Preliminary evidence from this short-term trial therefore suggests that valbenazine is relatively safe for patients with mental illness.

Does every patient with tardive dyskinesia deserve a trial of valbenazine?

For psychiatrists and other prescribing clinicians, deciding whether to start a new medication is always based on an analysis of potential risks and benefits. Although the impact of valbenazine on TD for the average patient appears to be modest, patients with clinically significant TD deserve a trial of valbenazine so long as the known risks remain minimal. If the speculation that valbenazine could have a salutary effect on psychotic symptoms themselves turns out to be true, then that would provide an additional rationale to try valbenazine as an add-on treatment option for those with TD.

When deciding whether to try a new medication, it's also important to consider how it compares to other treatment options. While no other medications have ever FDA approved for the treatment of TD, some have shown promise and some are routinely used through “off-label” prescribing. For example, the antipsychotic medication clozapine appears to be effective for TD and in particular for a variant called “tardive dystonia.” Because of its serious and potentially life-threatening side effects, clozapine is only FDA-approved for patients with “treatment refractory” schizophrenia who have not responded to other antipsychotic medications. For patients with treatment refractory schizophrenia who have persisting and troubling psychotic symptoms and are also suffering from TD, clozapine should be considered as a treatment option. How clozapine might compare to valbenazine for the treatment of TD requires a direct “head to head” study.

Tetrabenazine and deutetrabenazine are other VMAT2 inhibitors FDA-approved for Huntington's disease, but unlike valbenazine, they are not approved for TD and have "black box" warnings that must be considered when weighing risks against potential benefits. 

Just how many patients with TD should receive a trial of valbenazine is literally the “million dollar question.” Valbenazine has not yet been released, but like any new drug, it will probably be expensive when it comes to market. Recommending valbenazine for a individual patient is a relatively easy decision to make for a clinician, but within the larger scope of healthcare, the financial cost of a new medication must be weighed against its modest average benefits. Although the prevalence of TD has not been well-quantified, the large number of people in the US treated with antipsychotic medications for one reason or another suggests that the number of people with TD can be measured in the hundreds of thousands (one study reported a rate of as much as 1.8 per 1000 individuals2). That means that the potential market for valbenazine is sizable, especially if some clinicians start to use valbenazine “off-label” for not just treatment of TD, but prevention. The potential market size for valbenazine is why a pharmaceutical company has gone to the trouble and expense of developing the first-ever FDA-approved treatment for TD, but leaves open the question of the financial impact of starting such a large number of patients on a new drug. Healthcare systems, insurance companies, and governmental agencies will have to ponder this in the months to come.

The author reports no conflicts of interest related to the subject of this blogpost, including no affiliation with Neurocrine Biosciences or any other pharmaceutical company. 


Dr. Joe Pierre and Psych Unseen can be followed on Facebook and Twitter.


1. Hauser RA, Factor SA, Marder SR, et al. KINECT 3: A phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia. American Journal of Psychiatry 2017.

2. Merrill RM, Lyon JL, Mataico PM. Tardive and spontaneous dyskinesia incidence in the general population. BMC Psychiatry 2013; 13:152.

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