Christoph U. Correll, MD
The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell

Key Takeaways

  • The most effective treatment of tardive dyskinesia (TD) is prevention, either by avoiding dopamine antagonist (antipsychotic) therapy or by discontinuing therapy at the first signs of TD.
  •  Before the introduction of vesicular monoamine transporter 2 (VMAT2) inhibitors, TD was largely untreatable.
  • Two VMAT2 inhibitors, deutetrabenazine and valbenazine, are effective against TD, with more than one-half of patients achieving a 30% or greater reduction in symptoms and one-third reaching symptom reduction of 50% or more.
  • Long-term data on both drugs show extended efficacy with 1 to 2 years of treatment.

Christoph U. Correll, MD, is professor of psychiatry and molecular medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, medical director of the Recognition and Prevention (RAP) program at Zucker Hillside Hospital, and professor and chair of the Department of Child and Adolescent Psychiatry at Charité University Medicine in Berlin, Germany. His research focuses on the identification, characterization, and psychopharmacologic management of adults and youth with severe psychiatric disorders.

Can you briefly review the history of the new VMAT2 inhibitors?

The first 2 VMAT2 inhibitors with an indication for the treatment of TD, deutetrabenazine and valbenazine, were approved by the Food and Drug Administration (FDA) in 2016. However, even before the currently used antipsychotic medications came into play, we knew of reserpine, an irreversible VMAT inhibitor that depletes the brain of dopamine. Patients undergoing treatment with reserpine no longer experience TD, but they also don’t experience drive, motivation, or a sense of reward. Instead, they experience depression, parkinsonism, and akathisia. As a result of this, VMAT inhibitors were put aside for decades. Neurologists have been prescribing the first reversible VMAT2 inhibitor, tetrabenazine, which was approved by the FDA for the treatment of Huntington chorea in 2008, off-label for TD. We as psychiatrists, however, only rarely used tetrabenazine, because it has a black box warning regarding an increased risk for depression and suicidality in patients with Huntington chorea, and there is no controlled evidence for the efficacy of tetrabenazine in patients with TD. Only with this new discovery of improved reversible VMAT2 inhibitors [deutetrabenazine and valbenazine] that are effective and safe for the treatment of TD have mental health providers become aware of VMAT-2 inhibitors — but many providers are still not that aware of them.

What is the pathogenesis of TD?

We do not know the exact cause of TD, but we have a few ideas. The ongoing hypothesis is that dopamine blockade leads to an upregulation of postsynaptic dopamine receptors and that this upregulation is somehow disconnected and is autonomously taking place. There is also the idea that there might be some interneuronal damage, such that there is a disbalance between excitation and inhibition in brain circuits having to do with movement. Another theory is that oxidative stress or inflammation plays a role in the pathophysiology of TD. These hypotheses seem reasonable and are related to data from animal models.


Only with this new discovery of improved reversible VMAT2 inhibitors [deutetrabenazine and valbenazine] that are effective and safe for the treatment of TD have mental health providers become aware of VMAT-2 inhibitors — but many providers are still not that aware of them.

Is TD related to dopamine antagonist therapy only?

Even before antipsychotic agents (or dopamine blockers) were developed, psychiatrists were seeing dyskinesias related to schizophrenia. Therefore, this misbalance in dopamine signaling seems to also affect patients with schizophrenia who are not exposed to dopamine blockade. But dopamine blockers have clearly been associated with TD, and the largest family of dopamine blockers are the antipsychotic agents.
 
There are several risk factors for TD. One is too much dopamine blockade acutely, which translates into extrapyramidal adverse effects, such as parkinsonism, dystonia, or akathisia — signs that the medication blocked the dopamine receptors too much or that the dopamine system is too sensitive and is reacting very strongly.1 Anticholinergic medications that we use to counter the parkinsonism are another marker of TD risk. What we do not know is whether it is the anticholinergic signal itself or that we blocked dopamine too much that prompted the anticholinergic use. Other risk factors are the use of first-generation agents that block dopamine unopposed by serotonin blockade, higher doses of dopamine-blocking agents, and longer duration of treatment. In addition to these treatment factors, patient factors related to higher TD risk have also been identified; these include female sex, older age, mood disorder diagnoses (at least with first-generation antipsychotic use), diabetes, and substance use.

How do the earlier therapies compare with VMAT2 inhibitors?

The pharmacologic therapies used before the 2 approved VMAT2 inhibitors, deutetrabenazine and valbenazine, were really not effective for TD. The most effective therapy is prevention — that is, not starting a dopamine blocker. Prevention is key. We want to ensure that we prescribe dopamine blockers only when they are really needed and for the time that is needed. Prevention also includes using conservative doses, using second-generation drugs over first-generation antipsychotics, and informing patients and caregivers of the risk for TD, so that we can identify the emergence of TD early and act appropriately. The strategies used before the advent of VMAT2 inhibitors were stopping the antipsychotic agent, decreasing the dose (which often increases TD), or increasing the dose to mask the TD (although after a while there will likely be breakthrough of the involuntary movements). Some experimental therapies are being used but without any high-level evidence, including benzodiazepines, antioxidants, and free radical scavengers like vitamin E, vitamin B6, gingko biloba, and fish oil. Some people have also used melatonin.
 
Clinically, however, we felt that nothing worked for TD once it had developed. Tetrabenazine, a reversible VMAT2 inhibitor, has been used by neurologists and movement disorder specialists, but tetrabenazine comes with a lot of baggage. It has to be given 3 times a day owing to its short half-life, it has high peak and low trough levels, and the high peak levels have been associated with off-target activity. It is not just VMAT2 inhibition that occurs with tetrabenazine. There are actually 4 parts to the molecule, and 2 of them block dopamine postsynaptically, so the patient can develop extrapyramidal side effects and akathisia. Tetrabenazine also carries a black box warning regarding the risk for depression and suicidality when used for the treatment of patients with Huntington chorea, for which tetrabenazine is approved, and this has concerned psychiatrists.

How do the 2 newly approved reversible VMAT2 inhibitors, deutetrabenazine and valbenazine, differ from tetrabenazine?

In deutetrabenazine, a hydrogen atom in tetrabenazine is replaced with deuterium, a stable, nonradioactive, nontoxic, and naturally occurring isotope. This substitution alters the kinetics of the molecule in a favorable way. Deutetrabenazine still has 4 metabolites, but it can be given twice a day because it is harder to break down, leading to less peak–trough variation. As a result, there are few off-target effects that can lead to akathisia or parkinsonian symptoms. Deutetrabenazine also has no black box warning for treatment-related depression or suicidality when used for the indication in TD.
 
Valbenazine is based on a different approach. It is a prodrug that isolates the one component of tetrabenazine that acts as the VMAT2 inhibitor. It has been stripped of the other components that are postsynaptic dopamine blockers, eliminating the potential for off-target problems related to the risk for extrapyramidal symptoms or akathisia. Valbenazine can be given once a day, and no titration is needed, whereas deutetrabenazine requires a lengthy titration period. Valbenazine is started with one dose, 40 mg, which can be doubled after 1 week. Deutetrabenazine has to be given with food, whereas valbenazine does not.


Deutetrabenazine adverse effects
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Adverse effects commonly reported with deutetrabenazine include nasopharyngitis and insomnia.
Valbenazine adverse effects
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The adverse effect most commonly reported with valbenazine is somnolence.

How effective are these newer agents in treating TD?

Both of these reversible VMAT2 inhibitors are really effective for the treatment of TD. We have good data against placebo with both drugs showing that they each reduce the severity of TD by a significant degree. The pooled effect size is about 0.5, which is a medium effect size.2,3 What is interesting is that the trials for these drugs both used centralized ratings, which is a methodologic innovation for FDA-approval trials. This approach made it possible to reduce the placebo effect because the raters were watching videotaped examinations on the abnormal involuntary movement scale (AIMS) and had to come to consensus to deliver ratings, masked as to whether it was the beginning or the end of treatment. This careful assessment of TD severity is important, because the frequency and intensity of involuntary movements can fluctuate throughout the day and over weeks, even without treatment. The effect size was striking. The response rates were also relevant with at least one-half of patients experiencing a 30% reduction in symptoms of TD and one-third experiencing reductions of 50% or more.
 
It is also relevant in TD to recognize that effectiveness is not just about decreasing the total AIMS score: It is also very much about location, location, location. The impairment and distress patients experience with some twitching of the toes differs from that experienced with movements that affect the hands — which are readily seen by others and that impair the ability to write or type — or abnormal movements of the tongue — which result in inability to swallow or speak properly. Additionally, any involuntary movements in the face can be socially stigmatizing. Even a small reduction in the right area can make a huge difference in the quality of life and functionality of patients with TD.

How long do the effects last?

Beyond the short-term, placebo-controlled trials that lasted 6 weeks for valbenazine and 12 weeks for deutetrabenazine, there are long-term data that extend to 1 to 2 years of open treatment.2-5 In these studies, which mainly focused on safety, approximately 75% of patients reported that they were much or very much improved from baseline at the end of 2 years. That is a pretty strong statement. After the first 6 months, already approximately 50% of patients reported much or very much improvement in their TD symptoms, increasing to about two-thirds at 1 year and three-quarters at 2 years.4,5 These results underscore the real-world effectiveness of these 2 treatments.
 
However, data have also shown that when treatment with valbenazine or deutetrabenazine is stopped, the TD symptoms recur and return in severity to almost baseline levels.1,4,6 This means that if patients benefit from treatment with VMAT2 inhibitors, they generally will have to continue the treatment. The case might be different if we could stop the offending dopamine blocker, but this is often not possible. Thus, in general, patients with TD whose symptoms benefit from VMAT2 treatment will need to continue the therapy long-term.

This Q&A was edited for clarity and length.

Disclosure

Christoph U. Correll, MD, reported affiliations with AbbVie, Acadia Pharmaceuticals Inc., Alkermes Plc, Allergan Plc, Angelini Pharma, Aristo Pharma GmbH, Axsome Therapeutics, Cardio Diagnostics Inc, Compass, Damitsa, Gedeon Richter Plc, Hikma Pharmaceuticals Plc, Holmusk, Intra-Cellular Therapies Inc, Janssen/J&J, Karuna Therapeutics, LB Pharmaceuticals Inc, H. Lundbeck A/S, MedAvante-ProPhase, MedinCell S.A., Merck & Co., Inc., Mindpax, Mitsubishi Tanabe Pharma Corporation, Mylan N.V., Neurocrine Biosciences, Inc., Noven Therapeutics LLC, Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Recordati, Relmada Therapeutics, Inc., Reviva Pharmaceuticals Holdings, Inc., ROVI Pharma Industrial Services, Seqirus, Servier Laboratories, SK Life Science Inc, Sumitomo Dainippon Pharma Co., Ltd., Sunovion Pharmaceuticals Inc., Supernus Pharmaceuticals, Takeda Pharmaceutical Company Ltd, Teva Pharmaceutical Industries Ltd., and Viatris Inc.

References

1. Solmi M, Pigato G, Kane JM, Correll CU. Clinical risk factors for the development of tardive dyskinesia. J Neurol Sci. 2018;389:21-27. doi:10.1016/j.jns.2018.02.012
 
2. Hauser RA, Factor SA, Marder SR, et al. KINECT 3: a phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia. Am J Psychiatry. 2017;174(5):476-484. doi:10.1176/appi.ajp.2017.16091037
 
3. Anderson KE, Stamler D, Davis MD, et al. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Psychiatry. 2017;4:595-604. doi:10.1016/S2215-0366(17)30236-5
 
4. Factor SA, Remington G, Comella CL, et al. The effects of valbenazine in participants with tardive dyskinesia: results of the 1-Year KINECT 3 extension study. J Clin Psychiatry. 2017;78:1344-1350. doi:10.4088/JCP.17m11777
 
5. Fernandez HH, Stamler D, Davis MD, et al. Long-term safety and efficacy of deutetrabenazine for the treatment of tardive dyskinesia. J Neurol Neurosurg Psychiatry. 2019;90(12):1317-1323. doi:10.1136/jnnp-2018-319918
 
6. Solmi M, Pigato G, Kane JM, Correll CU. Treatment of tardive dyskinesia with VMAT-2 inhibitors: a systematic review and meta-analysis of randomized controlled trials. Drug Des Devel Ther. 2018;12:1215-1238. doi:10.2147/DDDT.S133205

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Reviewed January 2022