patient care perspectives

Refractory or Difficult-to-Treat Tardive Dyskinesia

by Rakesh Jain, MD, MPH


Our featured expert notes the importance of optimizing the use of vesicular monoamine transporter 2 (VMAT2) inhibitors and addressing comorbidities that might mimic or contribute to tardive dyskinesia (TD). Some patients with refractory TD may also benefit from a referral to a neurologist specializing in movement disorders.

Expert Commentary

Rakesh Jain, MD, MPH

Clinical Professor
Department of Psychiatry
Texas Tech University Health Sciences Center School of Medicine - Permian Basin
Midland, TX

“Given the existing avenues for intervention and effective treatment, there should be few, if any, patients with TD today whose symptoms truly cannot be helped.”

Rakesh Jain, MD, MPH

For patients with TD who are receiving treatment but do not seem to be responding, there are a number of possibilities that should be explored before they are considered to be refractory to treatment. We now have the VMAT2 inhibitors valbenazine and deutetrabenazine, which are both effective, but it is important to confirm adherence to treatment. It is striking that many patients who have been labeled as being resistant to VMAT2 inhibitors are only partially adherent to their medications (eg, missing 20%-30% of their doses). So, the first rule is that we should not be too quick to conclude that a patient is treatment resistant. The second rule is to be sure that the patient is on the correct dose of the VMAT2 inhibitor. These rules are really important.

A third possibility is that there is a comorbidity involved. For example, Parkinson’s disease and TD often occur together, especially in older individuals. If you do not address both the TD and the comorbidity, the patient may not improve, even though there may have been a response to the TD component of the clinical picture.

If such comorbidities are absent and doses of the VMAT2 inhibitor have been optimized but the patient still has significant TD with impairment, there is a strong rationale for switching treatment to the other VMAT2 inhibitor. The 2 US Food and Drug Administration–approved agents are pharmacokinetically and—quite importantly—pharmacodynamically different. Resistance to one does not necessarily mean resistance to the other. So, patients should not be considered to be refractory to the class unless both agents have been tried at optimum doses for a sufficient length of time.

If patients still have TD symptoms and impairment, then referral to a movement disorder neurologist is warranted. Deep brain stimulation is an intervention that has been used in Parkinson’s disease, and I can testify firsthand (because I have met patients who have received it) that it can be very effective for tardive syndromes. In fact, a VMAT2 inhibitor can become more effective once the deep brain stimulation device has been implanted.

Given the existing avenues for intervention and effective treatment, there should be few, if any, patients with TD today whose symptoms truly cannot be helped.


Bhidayasiri R, Jitkritsadakul O, Friedman JH, Fahn S. Updating the recommendations for treatment of tardive syndromes: a systematic review of new evidence and practical treatment algorithm. J Neurol Sci. 2018;389:67-75. doi:10.1016/j.jns.2018.02.010

Kashyap S, Ceponiene R, Savla P, Bernstein J, Ghanchi H, Ananda A. Resolution of tardive tremor after bilateral subthalamic nucleus deep brain stimulation placement. Surg Neurol Int. 2020;11:444. doi:10.25259/SNI_723_2020

Krause P, Kroneberg D, Gruber D, Koch K, Schneider G-H, Kühn AA. Long-term effects of pallidal deep brain stimulation in tardive dystonia: a follow-up of 5-14 years. J Neurol. 2022 Jan 27. doi:10.1007/s00415-022-10965-8

Sajatovic M, Alexopoulos GS, Burke J, Farahmand K, Siegert S. The effects of valbenazine on tardive dyskinesia in older and younger patients. Int J Geriatr Psychiatry. 2020;35(1):69-79. doi:10.1002/gps.5218

Sajatovic M, Wilhelm A, Finkbeiner S, et al. Long-term safety and efficacy of deutetrabenazine in younger and older patients with tardive dyskinesia. CNS Spectr. 2021;26(2):157-158.

Stahl SM. Comparing pharmacologic mechanism of action for the vesicular monoamine transporter 2 (VMAT2) inhibitors valbenazine and deutetrabenazine in treating tardive dyskinesia: does one have advantages over the other? CNS Spectr. 2018;23(4):239-247. doi:10.1017/S1092852918001219

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