Sino-US expert summit dialogue, comprehensive exchange of frontier topics in diagnosis and treatment of tardive dyskinesia

*Only for medical professionals to read and refer to "Concentrate", discuss the diagnosis and treatment of tardive dyskinesia! Tardive Dyskinesia (TD) is a special and persistent extrapyramidal response, mainly manifested as involuntary movements of the mouth, lips, tongue and other parts, as well as dance-like movements of the limbs and trunk
.

TD is mainly caused by long-term use of dopamine receptor blockers (DRBAs) such as antipsychotic drugs (APs), and is more common in patients who have been taking APs for 1-2 years or more
.

As the prevalence of mental disorders in China is increasing year by year, there are a large number of patients who need long-term medication, and TD is becoming more and more common in clinical work
.

Clinicians should have an in-depth understanding of the diagnosis and differential diagnosis of TD, and timely use of new drugs and other means to conduct clinical intervention and management of patients [1]
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On November 22, 2021, the "Concentration - Sino-US Expert Summit Dialogue" co-organized by the "Medical Community" and Teva Pharmaceuticals ushered in a special session on "tardive dyskinesia".
The conference was organized by Yu Xin of Peking University Sixth Hospital.
The professor presided over the meeting, and invited Professor Wan Xinhua of Peking Union Medical College Hospital, Professor Si Tianmei of Peking University Sixth Hospital, and Professor Liu Tiebang of Shenzhen Mental Health Center to participate in the meeting, and invited Professor Rakesh Jain of Texas Tech University through online connection.
The topic of diagnosis and differential diagnosis of TD, interpretation of current diagnosis and treatment guidelines, and management strategies for TD symptoms and damages, etc.
, conducted wonderful academic exchanges and sharing
.

Part 1 Diagnosis and Differential Diagnosis of TD Professor Wan Xinhua from Peking Union Medical College Hospital shared on the topic of diagnosis and differential diagnosis of TD.
From the classical clinical definition, TD refers to the occurrence of TD after taking APs (≥ 3 months).
Abnormal motor symptoms, the diagnostic criteria for the 2013 American Academy of Neurological Disorders "Tail-onset Syndrome" Guidelines (AAN-TD), also require patients to have "moderate" involuntary abnormal movements in at least one body part or "" Mild" involuntary abnormal movements, and other incentives have been excluded [2]
.

In addition to APs and other dopamine receptor antagonists, the pathogenesis of TD may also be related to drugs such as antiemetics, calcium channel antagonists, and some antihypertensive drugs
.

Due to different diagnostic criteria, population characteristics and other reasons, the prevalence and incidence of TD are difficult to calculate, and the data of previous studies vary greatly.
Currently, it is believed that the prevalence of TD in patients taking APs outside the hospital can reach 30%, and the annual incidence rate is about 4%.
-8%, depending on the type of medication and population characteristics of patients, about 2% of patients can spontaneously relieve each year
.

The use of atypical APs may reduce extrapyramidal reactions and reduce the incidence of TD, but the clinical management of TD is still challenging
.

Tardive dystonia and TD often accompany, the following are the identification points of tardive dystonia and primary dystonia
.

Table 1.
Differential diagnosis of tardive dystonia and primary dystoniaPart 2 Interpretation of TD diagnosis and treatment guidelines After the release of the classic AAN-TD guidelines in 2013, the Chinese Guidelines for the Prevention and Treatment of Schizophrenia (2015 Edition), the Canadian Neurological Association (CPA) Consensus on the Treatment of Tardive Movement Disorders (2019 Edition) [3], and Japan's "Guidelines for the Prevention and Treatment of Schizophrenia (2015 Edition)" Guidelines and consensuses such as "Expert Consensus on Drug Treatment of Schizophrenia" all involve the diagnosis and treatment of TD.
For example, China (see Figure 1) and Japanese guidelines for schizophrenia list TD as a common extrapyramidal adverse reaction of APs treatment, and its treatment should be and diagnosis also provide corresponding recommendations [4]
.

Figure 1.
Recommendations for the prevention and treatment of TD in the 2015 edition of the Chinese Guidelines for the Prevention and Treatment of Schizophrenia The 2013 edition of the American AAN guideline [2] specifically for TD, mainly raised a number of questions around the clinical treatment of TD, such as discontinuing typical DRBAs or converting to Whether atypical DRBAs can reduce TD symptoms, the efficacy of other drugs for TD, and whether botulinum toxin injection or surgical treatment can benefit patients (see Figure 2)
.

Figure 2.
The core points of the 2013 AAN-TD treatment practice guidelines in the United States.
For example, in the drug treatment section, the 2013 version of the AAN-TD guidelines believes that there is insufficient evidence for discontinuing APs or switching to atypical DRBAs to relieve TD symptoms, and the safety of first-generation APs treatment Sexual risks outweigh short-term benefits, and some second-generation APs themselves may also cause TD, masking the patient's symptoms, so treatment limitations are common
.

The 2013 edition of the AAN-TD guidelines did not give the highest level of A-level recommendation for any drug, some antioxidants and GABA inhibitors received a B-level recommendation, and tetrabenazine as a dopamine depleting agent also received a C-level recommendation in the guidelines.

.

Based on the evidence-based medical evidence provided by the latest research, the AAN-TD guidelines were also updated in 2018 [5].
The recommendations for discontinuation/switching of DRBAs remain unchanged, and the recommended levels of drug therapy in the 2013 version of the guidelines are basically followed.
However, for the first time, the guidelines have added a level A recommendation, that is, the highest level recommendation for the vesicular monoamine transporter-2 (VMAT2) inhibitors deuterotetrabenazine and valbenazine
.

Figure 3.
The latest update of the 2018 American AAN-TD guidelines for drug treatment recommendations.
AAN-TD guidelines recommend high-level deuterium tetrabenazine, mainly based on two randomized controlled, multi-center clinical phase III studies of ARM-TD and AIM-TD [ 6-7], and the follow-up results of two extended follow-up studies of RIM-TD and OLE [8-9], in the ARM-TD/AIM-TD study, patients started 2-4 weeks of deuterium , Abnormal Involuntary Movement Scale (AIMS) scores can be significantly improved, and the improvement is greater at 12 weeks of treatment than the control group, and when the treatment period is extended to 106 weeks and 145 weeks, deuterotetrabenazine can still maintain a good effect.
and safety (see Table 2)
.

Table 2.
Summary of key clinical research evidence for deuterotetrabenazine in the treatment of TD The TD symptoms of patients taking APs should be evaluated and followed up to minimize or avoid the risk of drug-related TD.
For patients with a clear diagnosis, they should refer to the diagnosis and treatment path for standardized treatment as soon as possible, and first-line drugs such as deuterotetrabenazine should be used
.

Figure 4.
Part 3 of the clinical diagnosis and treatment path proposed by the AAN-TD guidelines is a two-pronged approach to simultaneously improve the symptoms and damage of TD disease.
Medication history, performance of involuntary movements and positive AIMS scale assessment, but lack of evaluation of the patient's quality of life and impact on life and social function, the "damage" caused by these TD symptoms will further affect the patient's life on the basis of mental disorders [10] (see Figure 5), increasing the burden of medical treatment, so clinicians must control TD symptoms, reduce the functional damage caused by symptoms to patients, and help patients return to daily life
.

Figure 5.
TD will further aggravate the impact on the quality of life of patients with different mental disorders.
Therefore, it is possible to intervene from the perspective of the mechanism of TD, and VMAT2 inhibitors that reduce patients' involuntary movements should become the main therapeutic drugs in clinical practice
.

In addition to the previously mentioned AAN-TD guideline treatment pathways, the 2019 Canadian TD Diagnosis and Treatment Consensus [3] also gives Class A recommendations for deuterazine and valbenazine, but attention should be paid to the use of VMAT2 inhibitors in clinical medication.
At the same time, effective communication between doctors and patients is carried out to help patients understand the risk-benefit situation of TD disease itself and VMAT2 inhibitor treatment, and improve the cooperation of patients and their families with treatment
.

In 2020, when the American Psychiatric Association (APA) formulated the guidelines for schizophrenia, the principles for the treatment of patients with TD also began to move closer to the guidelines such as AAN-TD, and the experts who wrote the guidelines unanimously recommended the use of VMAT2 inhibitors for patients with moderate to severe TD.
[11], and proposed to fully consider the clinical phenotype, symptoms and severity of original mental disorders of TD patients, patients' self-reported impairment of quality of life, antipsychotic drug treatment plans and other factors to consider treatment decisions (see Figure 6).
)
.

Figure 6.
Discussion and exchange of factors to consider in the treatment of TD symptoms in patients with schizophrenia In the question-and-answer session at the end of the conference, Professor Yu Xin of Peking University Sixth Hospital presided over, and the participating experts had a wonderful exchange on the following issues: 1.
How to improve the diagnosis and recognition rate of TD? Professor Liu Tiebang: Even in the era of second-generation APs treatment, the incidence of TD has only declined, and it has not moved away from the clinical environment.
However, clinicians may lack sufficient awareness of identifying TD symptoms and applying diagnostic tools such as the AIMS scale, resulting in Some patients are missed or misdiagnosed.
It is necessary to be more vigilant about TD, identify high-risk groups in advance, and consider regularly evaluating patients taking APs every six months to one year for TD screening, and make full use of diagnostic tools
.

2.
Under what circumstances is botulinum toxin injection suitable for patients with tardive dystonia? Professor Wan Xinhua: For some patients with tardive dystonia who have severe symptoms and meet the treatment indications, symptomatic treatment can be given by injecting botulinum toxin to relieve the symptoms of tardive dystonia caused by excessive muscle contraction in patients with tardive dystonia.
It is more effective for patients with more limited symptoms
.

3.
What is the efficacy and safety of deuterotetrabenazine in the treatment of TD? What was your experience with the application in the US? Professor Si Tianmei: Tetrabenazine was modified by deuterium tetrabenazine, and the hydrogen atoms of the 2 methoxy groups in the tetrabenazine molecule were replaced by deuterium atoms, which effectively improved the selection of drugs for VMAT2 It can significantly reduce the level of dopamine in patients, and is more suitable for precise intervention of TD, so that it has better efficacy and safety in clinical research
.

Professor Rakesh Jain: The currently approved dose of deuterium tetrabenazine is divided into 7 dose gradients, so the dose can be flexibly adjusted according to the severity of the patient's symptoms.
I think Chinese counterparts pay attention to titrating the dose from low to high, but also Boldly use high-dose therapy to restore the patient's life function and quality as much as possible
.

We do not adjust the dose of tetrabenazine in the U.
S.
based on how the patient is taking APs, because tetrabenazine acts on neurons presynaptic and APs act on synapses.
Finally, there is no mechanistic basis for the drug interaction between the two
.

References: [1]Jackson R, et al.
Neuropsychiatr Dis Treat.
2021;17:1589-1597.
[2]Bhidayasiri R, et al.
Neurology.
2013;81(5):463-469.
[3]Ricciardi L, et al.
Can J Psychiatry.
2019;64(6):388-399.
[4]Sakurai H, et al.
Pharmacopsychiatry.
2021;54(2):60-67.
[5]Bhidayasiri R, et al 2018;389:67-75.
[6]Fernandez HH, et al.
Neurology.
2017;88(21):2003-2010.
[7]Anderson KE, et al.
Lancet Psychiatry.
2017;4 (8):595-604.
[8]Fernandez HH, et al.
J Neurol Neurosurg Psychiatry.
2019;90(12):1317-1323.
[9]Sajatovic M, et al.
Am J Geriatr Psychiatry.
2021.
[ 10] McEvoy J, et al.
Qual Life Res.
2019;28(12):3303-3312.
[11]Keepers GA, et al.
Am J Psychiatry.
2020;177(9):868-872.
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