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How to Combat Tardive Dyskinesia with VMAT2 Inhibitors

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For years, we have dreaded seeing our patients develop antipsychotic-induced tardive dyskinesia because there was little we could do about these symptoms. Thankfully, we now have new treatments that produce noticeable improvements in tardive dyskinesia. 

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Published On: 12/15/2021

Duration: 11 minutes, 23 seconds

Referenced Article:Finally, Effective Treatments for Tardive Dyskinesia,” The Carlat Hospital Psychiatry Report, April/May/June 2021

Victoria Hendrick, MD, and Zachary Davis, BS, have disclosed no relevant financial or other interests in any commercial companies pertaining to this educational activity.

Transcript: 

Dr. Hendrick: For years, we have dreaded seeing our patients develop antipsychotic-induced tardive dyskinesia, or TD, because there was little we could do about these symptoms. In 2017, the FDA approved two agents to treat TD, valbenazine (Ingrezza) and deutetrabenazine (Austedo), dramatically improving management options. A previous issue from The Carlat Hospital Psychiatry Report included a Clinical Update describing these two recently approved medications for antipsychotic-induced tardive dyskinesia. In this podcast, we will discuss the pros and cons of these two medications, as well as some other treatment options, for tardive dyskinesia, and what factors should be considered when choosing a tardive dyskinesia treatment for your patients.

Welcome to The Carlat Psychiatry Podcast

This is a special episode from The Carlat Hospital Psychiatry Report.

I’m Dr. Victoria Hendrick, the Editor-in-Chief of The Carlat Hospital Psychiatry Report, and a clinical professor at the David Geffen School of Medicine at UCLA. I’m also the director of inpatient psychiatry at Olive View — UCLA Medical Center.

Zachary Davis: And I’m Zachary Davis. I graduated from UC Santa Cruz with a BS degree in neuroscience, and I’m a content-coordinator at The Carlat Report. I write CME questions, podcast scripts, and I edit podcasts too. I’m also a pre-med student who’ll be applying to medical school next year, and I’ll be joining Dr. Hendrick on this podcast.

So Dr. Hendrick, what are the symptoms of tardive dyskinesia?

Dr. Hendrick: Tardive dyskinesia is characterized by abnormal, involuntary, and often repetitive, movements of different areas of the body, and can be caused by chronic antipsychotic therapy. More specifically, the chronic blockade of dorsal striatal D2 receptors in the in-direct pathway of the extrapyramidal system by antipsychotics can cause tardive dyskinesia. 

Zachary Davis: Okay, so, how do these recently approved VMAT2 inhibitors combat the pathophysiology of tardive dyskinesia? And are there any particular antipsychotics that are more likely to cause tardive dyskinesia?

Dr. Hendrick: To answer you first question, deutetrabenazine and valbenazine inhibit the vesicular monoamine transporter 2, aka VMAT2, depleting the amount of serotonin, norepinephrine, and — most important for TD symptom reduction — dopamine present in presynaptic vesicles. 

And, yes, research indicates that first generation antipsychotics are more likely to cause tardive dyskinesia than second generation antipsychotics. It’s believed that the higher affinity of typical antipsychotics for the striatal dopamine D2-receptor possibly contributes to the increased incidence of tardive dyskinesia in patients treated with first generation antipsychotics, compared to those given atypicals. 

Zachary Davis: Are there any other available VMAT2 inhibitors besides the two recently approved ones?

Dr. Hendrick: There is another VMAT2 inhibitor, called tetrabenazine (Xenazine), which has been available for years as an approved treatment for the chorea associated with Huntington’s Disease. It is available as a generic and costs about $400/month vs. about $6000/month for the two recently approved medications. 

Zachary Davis: So why don’t we just use tetrabenazine? I mean, $6000/month is extremely expensive.

Dr. Hendrick: Yes, there is a huge price discrepancy between the two approved drugs and tetrabenazine, but tetrabenazine has not been rigorously tested for efficacy in TD. Deutetrabenazine and valbenazine have longer half-lives and can be dosed once or twice daily, compared to tetrabenazine’s three times daily dosing needed to mitigate fluctuating plasma concentrations and an “on-off” phenomenon when doses wear off. 

Zachary Davis: Are there any other strategies for tardive dyskinesia management, besides the use of VMAT2 inhibitors?

Dr. Hendrick: There are definitely a few alternative strategies that might improve outcomes in tardive dyskinesia. These include switching from a first generation to a second-generation antipsychotic, if possible, considering that the prevalence of tardive dyskinesia with second generation antipsychotics is approximately 20% compared to 30% with FGAs. You can discontinue any anticholinergic drugs (e.g., benztropine, trihexiphenidyl) as these may worsen symptoms. You can  also consider alternative therapy with agents that also have evidence of efficacy for TD, especially for patients who don’t have access to VMAT2 inhibitors or when suicidality may be a concern. These include amantadine, vitamin B6 and vitamin E.

Zachary Davis: The reason why suicidality might be a concern is because deutetrabenazine and tetrabenazine have a black box warning for increased risk of depression and suicidality in patients with Huntington’s disease.

Dr. Hendrick: Additionally, clinicians should Screen for tardive dyskinesia with the Abnormal Involuntary Movement Scale, or AIMS, every 3 – 6 months, to improve your likelihood of catching this syndrome early or to monitor it’s severity in patients who already suffer from this syndrome.

Zachary Davis: Okay, now that we’ve covered the basics of tardive dyskinesia, and it can be treated, let’s dive into the evidence of efficacy for the VMAT2 inhibitors in tardive dyskinesia.

Dr. Hendrick: According to randomized controlled trial data submitted to the FDA, in the first 6-12 weeks of treatment, valbenazine (40 – 80 mg/day) and deutetrabenazine (24 – 48 mg/day) reduced AIMS scores by over 3 points, or about 30%, in patients with moderate to severe TD, which was defined as having an AIMS score of >6. Both drugs produced noticeable improvements by week 2, and patients’ symptoms lessened progressively over time, dropping by as much as 6 points over the course of two years. 

Zachary Davis: Additionally, higher doses of these two medications have been shown to be more effective in tardive dyskinesia than that of lower doses. 

Dr. Hendrick: That’s right. For example, among patients on 80 mg of valbenazine, 40% showed ≥ 50% improvement at week 6, in contrast to 24% of patients on 40 mg/day.

Zachary Davis: So Dr. Hendrick, will patients maintain treatment benefits after they’ve discontinued these drugs?

Dr. Hendrick: Unfortunately, most patients’ symptoms return to baseline within 4 weeks of drug discontinuation, although for unclear reasons, about one in six patients do seem to maintain the response.

Zachary Davis: What are the side effects associated with these two drugs?

Dr. Hendrick: Overall, valbenazine and deutetrabenazine are well tolerated, with somnolence, dry mouth, headache, akathisia and urinary tract infections being the most common adverse effects. In clinical trials, drug discontinuation due to side effects was comparable between the active drugs and placebo.

Zachary Davis: Patients receiving doses above 24 mg/day of deutetrabenazine along with other QT prolonging drugs should have a baseline and follow-up EKG with dose increases. Patients must also be monitored for worsening depression and suicidality, but again, these problems have mainly been observed in patients being treated for Huntington’s disease.

What about drug interactions? Are there any drugs that we want to avoid using with these VMAT2 inhibitors?

Dr. Hendrick: Definitely. We want to avoid using any VMAT2 inhibitor with monoamine oxidase inhibitors. And both valbenazine and deutetrabenazine have drug interaction potential with multiple drugs, like MAOIs, carbamazepine, phenytoin, St John’s wort, so be sure to check for drug interactions before prescribing. 

Zachary Davis: Are there any specific conditions where clinicians may want to adjust their doses of VMAT2 inhibitors? 

Dr. Hendrick: Yes. there are. If the patient is on a strong CYP2D6 inhibitor, valbenazine should be capped at 40 mg, deutetrabenazine at 36 mg, and tetrabenazine at 50 mg. Additionally, for valbenazine, the dose should also be capped at 40 mg if the patient is on a strong 3A4 inhibitor. 

 Zachary Davis: Dr. Hendrick, what should clinicians consider when choosing a VMAT2 inhibitor for tardive dyskinesia?

Dr. Hendrick: Since there are no head-to-head trials comparing efficacy, your choice of drug will depend on cost, ease of procurement, contraindications, and avoidance of drug interactions. Adverse effects are similar between both agents. Some patients might prefer valbenazine as it is dosed daily versus the twice daily dosing of deutetrabenazine.

Both drugs are expensive and insurance policies do not always cover them so some patients will be unable to afford these medications. You can prescribe generic tetrabenazine as an alternative, which, at this point is less than a tenth the price of the two approved drugs. 

Zachary Davis Any final thoughts on this topic?

Dr. Hendrick: The VMAT2 inhibitors are game changers in the treatment of tardive dyskinesia, especially for patients with moderate to severe tardive dyskinesia. This syndrome is debilitating, and often has the effect of causing a significant degree of embarrassment or worry in social settings for patients who are afflicted by it. These VMAT2 inhibitors can really improve outcomes in tardive dyskinesia and improve the overall well-being of our patients. 

Dr. Hendrick: This Clinical Update is available for subscribers to read in The Carlat Hospital Psychiatry Report. Hopefully people check it out. Subscribers get print issues in the mail and email notifications when new issues are available on the website. Subscriptions also come with full access to all the articles on the website and CME credits. 

Zachary Davis And everything from Carlat Publishing is independently researched and produced. There’s no funding from the pharmaceutical industry. 

Dr. Hendrick: That’s right, the newsletters and books we produce depend entirely on reader support. There are no ads and our authors don’t receive industry funding. That helps us bring you unbiased information you can trust. 

Zachary Davis: Go to www.thecarlatreport.com to sign up. You can get a full subscription to any of our four newsletters for $30 off using the coupon code LISTENER.

Dr. Hendrick: As always, the links you need are in the episode description. Thanks for listening and have a great day!

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