The harm of tardive dyskinesia should not be underestimated. The Chinese and American experts connect in the cloud to talk about new treatment methods!

*For medical professionals' reference only.
At the Sino-US Expert Summit (Special Session for Tardive Dyskinesia), Chinese and American experts conducted in-depth discussions on the management strategies for tardive dyskinesia.

Tardive dyskinesia (TD) is a special and long-lasting extrapyramidal reaction, mainly manifested as involuntary movements of the mouth, lips, tongue and other parts, as well as dance-like movements and dystonia of the limbs and trunk.

The disease is mainly caused by long-term use of dopamine receptor blockers (DRBAs) such as antipsychotic drugs.
Even if the drug is stopped, the symptoms of TD will not disappear completely, and may even worsen.

At present, there is no ideal treatment plan, prevention and early diagnosis and differential diagnosis are very important [1].

To improve the status quo of TD diagnosis and treatment and improve the quality of life of patients.

On March 23, 2021, Teva Pharmaceuticals will hold the Sino-US Expert Summit Dialogue (TD Special Session).
This meeting was hosted by Professor Yu Xin from Peking University Sixth Hospital, and specially invited Professor Wan Xinhua from Peking Union Medical College Hospital and Southern Medical University Nanfang Hospital Professor Zhang Bin and Professor Leslie Citrome of New York University School of Medicine shared in detail the current status of diagnosis and treatment and management strategies of TD.

Correct understanding of dyskinesia, distinguish primary and late-onset dystonia Professor Wan Xinhua from Peking Union Medical College Hospital shared the types and evaluation methods of dystonia, and introduced the clinical features and differential diagnosis of dystonia in detail.

Dyskinesias can be divided into two types.
One is mainly "little movement", including Parkinson's disease, gait disorders, and stiffness syndrome, etc.
; the other is mainly "hyperactivity", including tremor, muscle Dystonia, tics, dancing, myoclonus, etc.

In clinical evaluation of dyskinesia, first determine whether there is involuntary movement, whether it may be a purposeful voluntary movement, such as exaggerated posture, gesture or forced movement, or involuntary muscle tension to relieve pain.

Generally, involuntary movement can be aggravated by anxiety and tension, and reduced or disappeared during sleep.
Symptoms can be relieved by taking isopentobarbital or sleeping pills.

Dystonia is a form of dyskinesia, and it can also be an independent disease.
It is characterized by abnormal movements and/or postures caused by continuous or intermittent muscle contractions, often recurring.

Dystonic movement is generally a patterned twisting movement that can be combined with tremor.

Figure 1.
Movement characteristics of dystonia.
The core manifestations of dystonia are abnormal movements and abnormal postures, which are often induced or aggravated by voluntary movements, accompanied by excessive muscle activation.

Early in the course of the disease, symptoms can be unexpectedly improved due to some sensory stimulation, which is called "sensory tricks.
"
Figure 2.
Movement characteristics of dystonia.
Dystonia can be divided into late-onset and primary.

There is no high incidence of late-onset dystonia, with an average age of 40 years.
Focal symptoms include delayed torticollis, delayed blepharospasm, and neck back.
The patient progresses from focal to full body within months or years Sex.

The age of onset of primary dystonia presents a bimodal distribution.
Patients with onset in childhood are more likely to develop generalized dystonia, and patients with onset in adulthood are more likely to have focal or segmental dystonia.

Figure 3.
Differentiating between delayed and primary dystonia.
Once TD is diagnosed, clinical management should be carried out according to the existing diagnosis and treatment pathways.
Professor Zhang Bin from Nanfang Hospital of Southern Medical University introduced the diagnostic criteria and risk factors of TD, and Interpretation of TD-related guidelines and consensus at home and abroad.

In clinic, according to Schooler-Kane criteria, the involuntary abnormal movement scale (AIMS) can be used to diagnose TD[2].

The TD diagnostic criteria established by the American Academy of Neurology (ANN) guidelines in 2013 are: intermittent or uninterrupted use of antipsychotics for at least 3 months; presence of moderate involuntary abnormal movements in at least one body part (AIMS score 3 points), Or at least two body parts have mild involuntary abnormal movements (AIMS score 2 points); involuntary abnormal movements of limbs caused by other reasons can be ruled out [3].

Studies have found that the risk factors for TD include advanced age, women, smoking, alcohol abuse/dependence, mental illness, first-generation antipsychotic (FGA) treatment-related> second-generation antipsychotic (SGA) treatment-related, etc.
[4- 6].

The 2020 American Psychiatric Association (APA) guidelines point out that any antipsychotics on the market may have TD, and the risk of TD in adult patients treated with FGA may be three times the risk of TD related to the application of SGA [6].

Figure 4.
Risk factors for the onset of TD.
The 2015 "Second Edition of Chinese Guidelines for Schizophrenia Prevention and Treatment" pointed out that in the long-term treatment of antipsychotics, the side effects of TD and metabolism have the greatest impact on the patient's body and mind.
These two side effects need to be continuously monitored.
, Once it appears, it should be dealt with as soon as possible.

Some TDs are irreversible and still exist even after the drug is stopped.
There is currently a lack of effective drugs for the treatment of TD.
The principle of treatment for them is to first switch to a SGA with a low probability of TD, and use other drugs when necessary.

It is not recommended to use anticholinergic drugs, which can worsen symptoms [7].

Regarding the drug treatment of TD, the 2013 AAN "Clinical Practice Guidelines for Tardive Dyskinesia" recommended that the use of dopamine exhaustion agent tetrabenazine (C-level recommendation) can be considered.
Amantadine combined with antipsychotic drugs can be used for short-term treatment of TD ( C-level recommendation).

It is recommended to use risperidone or olanzapine with caution (U-level recommendation), thipromazine, morpholinone, sulpiride, haloperidol, acetazolamide, reserpine and α-methyldopa are inadequate in the treatment of TD (U Level recommendation) [8].

In 2018, the AAN "Clinical Practice Guidelines for Tardive Dyskinesia" updated the evidence, and the original guideline recommended drug ratings remain unchanged for TD drug treatment.

Added deuterium tetrabenazine and valbenazine as A-level recommendations [9].

Table 1.
2018 American AAN Guidelines TD Clinical Diagnosis and Treatment Path Deuterium tetrabenazine is a new type of VMAT2 inhibitor, which is an innovative deuterated drug.

Deuterium tetrabenazine has been proven to have good efficacy and safety in clinical trials [9].

Table 2.
Key overseas studies of deuterium tetrabenazine are summarized by Chinese and foreign guidelines and consensus recommendations.
Once TD is clearly diagnosed, standardized treatment should be carried out as soon as possible.

The 2018 U.
S.
AAN guidelines recommended VMAT-2 inhibitors as the first-line recommended drugs for TD.

It is recommended to manage TD according to the existing diagnosis and treatment path.

TD clinical management: five steps to success Professor Leslie Citrome from New York University School of Medicine shared the TD clinical management strategy, including diagnosis, evaluation, harm reduction, intervention and follow-up.

The first is correct diagnosis.

TD and drug-induced Parkinson's syndrome (DIP) are very common clinically, accounting for about 20% to 35% of patients taking antipsychotic drugs, and a higher incidence in special populations such as elderly patients.

DIP is manifested by slow movement and muscle stiffness, while TD is manifested by non-rhythmic twitches.

DIP usually appears a few weeks after medication, while TD usually appears after three months of taking antipsychotic drugs.

DIP can be relieved after the drug is stopped, but TD will continue after the drug is stopped, and may be accompanied for life.

Figure 5.
The correct diagnosis of TD is followed by evaluation.

AIMS is generally used clinically to assess the severity of TD.

AIMS contains 12 items, and it takes about 5-10 minutes to complete all items.

During the epidemic, patients can be assessed remotely through video.

It is recommended that the family members of the patient help the filming.
The patient is best to sit on a chair without armrests.

Figure 6.
Remote assessment of TD The third is to reduce harm.

In order to reduce the risk of TD, it is necessary to ensure and record the indications of DRBAs and use maintenance doses.

Figure 7.
Reduce the risk of TD.
The fourth is intervention.

For patients with TD, first consider discontinuing antipsychotic drugs.

Discontinuation of the drug may cause 33% to 53% of patients to worsen TD at the beginning, but after a period of time, 36% to 55% of patients will be relieved.

If the patient is unable to stop the antipsychotic drugs, the medication can be changed or the dosage of the antipsychotic drugs can be reduced.

Figure 8.
The final intervention method is follow-up.

During follow-up, AIMS can help clinicians understand the patient's treatment effect.

If the effect is not good, the treatment measures need to be adjusted in time.

However, the AIMS assessment alone is not enough.
It is also necessary to ask about the impact of involuntary exercise on the patient’s life, work and leisure.

In the question-and-answer session at the end of the conference, Professor Leslie Citrome answered the questions of the participating medical workers in detail: 1.
There are 3 dosage forms of deuterium tetrabenazine on the market in China: 6mg, 9mg and 12mg.
What titration rate should be used? How to choose the appropriate dosage range? Answer: Generally use 6mg bid to start the titration, increase to 9mg bid after one week, and increase to 12 mg bid after two weeks.

24-36 mg daily is a reasonable level, and some patients can use 24 mg bid.

The curative effect achieved by different drug doses varies from person to person, and the appropriate level should be selected according to the patient's response to the drug.

2.
Many TD patients cannot stop using antipsychotic drugs.
Will adding deuterium tetrabenazine aggravate the symptoms of psychosis? Can the dosage of antipsychotic drugs be adjusted when using deuterium tetrabenazine? Answer: In clinical trials of deuterium tetrabenazine, many patients continue to use antipsychotic drugs.
Adding deuterium tetrabenazine did not make the patients' condition worse, and the proportion of depression and suicide was no different than that of the placebo group.

Therefore, deuterium tetrabenazine can improve TD without changing the patient's original psychotic symptoms.

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[9]Bhidayasiri R, Jitkritsadakul O, et al.
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Tardive Dyskinesia Diagnosis and Treatment Practice Survey Questionnaire This questionnaire is designed to investigate doctors’ cognitions about tardive dyskinesia diagnosis and treatment.

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