Dr Stanley CaroffStanley N. Caroff, MD
Although the development of tardive dyskinesia, an involuntary movement disorder caused by long-term use of dopamine receptor blocking drugs, may not be guaranteed with the use of antipsychotics, it is certainly a possibility.

For Stanley N. Caroff, MD, professor emeritus of psychiatry at the University of Pennsylvania’s Perelman School of Medicine, this is all too familiar. With a long career in the treatment of tardive dyskinesia, among other conditions, he knows the challenges faced by patients who develop the disorder and the nuances of treatment which must be distinguished by the physicians. Coupled with a lack of complete understanding of tardive, for or quite some time, these physicians also lacked real options for treatment until recent years.

To provide his perspective on the state of care for tardive dyskinesia, Caroff spoke with NeurologyLive about the condition and the available therapies, as well as some of the needs that remain unmet.

NeurologyLive: What’s the state of care for tardive dyskinesia?

Stanley N. Caroff, MD: It’s a new day in the management of tardive dyskinesia, and there is new hope for patients and practitioners. The problem had been that, for many years, there was a nihilistic sense about tardive dyskinesia. There was no approved treatment, many of the studies of possible treatments were inadequate or failed, and so there was not much to offer patients with TD. In addition, there was some degree of complacency among psychiatrists, because the newer antipsychotic drugs appear to pose less of a risk of causing this problem, so interest waned. But there are tens of thousands of patients who have tardive dyskinesia from treatment in the past, and the newer antipsychotic drugs, although less likely to cause tardive dyskinesia, still have some risk. More importantly, the newer drugs are more widely used in the population, so there are many more patients now at risk from exposure to antipsychotic drugs. In view of the perceived clinical need and the failure of previous studies to confirm an effective treatment, commercial sponsors synthesized modified versions of tetrabenazine to treat tardive dyskinesia.

Tetrabenazine is an older drug that showed efficacy in reducing tardive dyskinesia but was limited by the need for frequent administration and by adverse effects including depression and parkinsonism. By altering the tetrabenazine molecule, which depletes dopamine in the brain by inhibition of vesicular monoamine transporter-2 (VMAT2), two promising drugs were developed. One is valbenazine (Ingrezza) and the other is deutetrabenazine (Austedo). State-of-the-art, randomized, placebo-controlled and double-blind trials were conducted which showed that both drugs were effective in reducing the symptoms of tardive dyskinesia significantly more than placebo, and furthermore, they had a better pharmacokinetic and safety profile compared to tetrabenazine. These trials provided convincing evidence for the FDA to approve these two drugs as effective and safe treatments for tardive dyskinesia.

The need that existed for approved treatments of tardive dyskinesia over decades has been met by these new drugs. But there are still significant issues. Clinicians need to re-learn how to recognize tardive dyskinesia, how to manage the overall psychopharmacology for patients who have tardive dyskinesia, and how to use these new drugs properly.

What are the remaining unmet needs despite the introduction of these new therapies?

We don’t have all the answers yet. These two new VMAT2 inhibitors are very helpful for practitioners, patients, and families as a treatment, but their introduction revitalized longstanding problems and questions about tardive dyskinesia that we still do not completely understand. We don’t know the mechanism underlying why tardive dyskinesia occurs and who is most likely to be affected. We still have to take steps to minimize the risk of tardive dyskinesia occurring, especially being more cautious about proper indications for use of antipsychotic drugs.

There also are questions concerning the long-term course and reversibility of tardive dyskinesia. The new treatments offer the chance to reduce the symptoms of tardive dyskinesia, which is a significant achievement —people don’t have to be embarrassed or impaired because of these movements. But questions remain; how many people might eventually recover from tardive dyskinesia? Does it ever go away? How long does that take? Which patients are likely to recover? How long do you have to continue the new drugs to suppress tardive dyskinesia? What can be done for people who don’t respond to or tolerate the VMAT2 inhibitors? So far, data emerging from longer-term studies show that the efficacy and safety of these drugs are maintained for at least one year. But it is also appears that symptoms of tardive dyskinesia return once the drugs are discontinued at least after one year. So, the long-term course, outcome and reversibility of tardive dyskinesia remains an important question.

Transcript edited for clarity.