• Tardive dyskinesia (TD) is characterized by involuntary movements of the body
• The face, lips, jaws, and tongue are most often affected.¹ However, movements of the upper extremities, lower extremities, and trunk can also occur
• TD differs from other movement-related extrapyramidal symptoms (EPS), such as drug-induced parkinsonism
• Patients with TD present with arrhythmic movements of the body parts listed above, whereas patients with parkinsonism present with rhythmic tremors, rigidity, and a shuffling gait²
• TD can have a devastating impact on patients' lives, interfering with their ability to carry out daily tasks, reducing their quality of life, and increasing social withdrawal³

Prevalence of TD in CATIE Schizophrenia trial. TD was diagnosed if modified Schooler-Kane TD criteria were met on at least 1 post-baseline AIMS assessment. Data from Miller DD, et al. Br J Psychiatry. 2008;193(4):279-288.

• TD can be observed with long-term treatment with dopamine receptor blocking agents such as antipsychotic agents^1,2
• First described in 1957 by Schonecker, about 5 years after the commencement of neuroleptic treatment in psychiatry^1,3
• Lower TD risk for second-generation antipsychotics (SGA) than for first-generation antipsychotics (FGA), but rates are not zero⁴

• TD can be associated with significant and often irreversible functional impairment and can also be socially stigmatizing - TD remains a significant treatment issue
• New treatment approaches to persistent TD - the VMAT2 inhibitors - are available, as approved by the US FDA for this purpose

Figure 1 | Method of action of VMAT2 inhibitors.
a | Normally, vesicular membrane transport type 2 (VMAT2) mediates loading of dopamine into synaptic vesicles for release. Breakdown of dopamine is mediated by monoamine oxidase.
b | VMAT2 inhibitors block transport of dopamine into synaptic vesicles, reducing dopamine release and depleting dopamine levels through its breakdown by monoamine oxidase.

VMAT2 is a protein concentrated in the human brain that is primarily responsible for re-packaging and transporting monoamines (dopamine, norepinephrine, serotonin, and histamine) in presynaptic neurons.

• Monique is a 27-year-old woman with bipolar disorder
• At a visit to her psychiatrist, she reports that her supervisor recently took her aside at work and complained that the "expressions" she has been making during department meetings are distracting
• Monique says she had been unaware that she was making unusual expressions, but since then she has also noticed that her legs are moving on their own when she sits at her desk
• She is currently taking a combination of risperidone and valproate daily for maintenance of her bipolar disorder, which included severe depressive episodes before she began treatment
• She has been taking this combination for a little over a year; she has never tried another treatment regimen, as this one has been controlling her bipolar symptoms well

Although TD is less prevalent with second-generation antipsychotics than with first-generation antipsychotics, it remains common. The use of antipsychotics is increasing, such as in the case of patients with bipolar disorder or major depressive disorder, and TD will continue to be seen.

While clinical examination is relevant and can reveal much in the recognition of TD, the AIMS takes only 5-10 minutes and is widely used for the routine, yet comprehensive, assessment of involuntary movements.

Benztropine can increase risk for or worsen TD.

• Increases risk of TD¹
• Can make TD worse¹
• Impairs cognition¹
• If patient needs it for more than a few weeks, then think of another antipsychotic that won’t require use of benztropine
• TD and drug-induced parkinsonism are sometimes mistaken for one another, but they respond very differently to treatment, including benztropine¹
• It is important to be able to distinguish between the two conditions, which can sometimes coexist within the same patient

Decreasing the dose of antipsychotics may ultimately reduce symptoms of TD; however, there may be worsening at first. In many cases the TD persists.

• Evidence indicates that decreasing the dose of antipsychotics, or discontinuing them entirely, ameliorates TD symptoms for many patients—but it may take time^1,2
• Dyskinesias can first appear after antipsychotic cessation and may disappear several weeks later; these symptoms, called withdrawal dyskinesia, reflect the action of antipsychotics to suppress or mask dyskinesia.³ If withdrawal dyskinesia persists, we call it TD
• Research shows that tapering off and discontinuing antipsychotics results in
  • Initial worsening of TD in 33–53% of patients¹
  • Long-term improvement in 36–55%¹
• However, we have limited randomized controlled trial-based evidence on this topic, so our understanding of the rate and timing of complete remission is uncertain
• It is difficult to justify continuing antipsychotic treatment in non-psychotic patients with TD. However, because the risk of psychotic relapse is significant among psychotic patients with TD,³ tapering or discontinuing antipsychotic treatment is often not an acceptable choice

Now let's move on...

to another case that requires important TD diagnostic and management decisions.

• Harold is a 53-year-old man with a history of schizophrenia
• Upon examination, Harold has puckering of the lips and sometimes sticks out his tongue
• When asked, Harold is unaware that he is making these movements
• Harold’s sister provides the history that these movements have been going on for several years and that everyone tends to stare at him when he is in public, and she feels embarrassed to be with him because of this
• Harold acknowledges that not many people talk to him and that at his visits to the clinic, no one sits next to him
• Harold’s hallucinations and delusions are under good control with his current medication regimen and he does not want to stop his medications; Harold’s sister provides additional history that Harold has become violent when medication changes were attempted

Age and cumulative exposure are important risk factors for development of TD in patients receiving an antipsychotic.

Major risk factors for TD include

• Age. Older individuals are at 4-5 times increased risk for TD (5% vs 20% per year)
• Cumulative exposure to dopamine receptor blocking agents, including commonly used agents such as metoclopramide, as well as antipsychotics. In the CATIE Schizophrenia Trial, the average number of years since first antipsychotic was 21.5 years for patients with TD vs 12.8 years for patients without TD (P<0.0001)¹

Minor risk factors for TD: female sex; race; preexisting mood, movement, or cognitive disorder; alcohol use; diabetes; human immunodeficiency virus (HIV) positivity²

• The occurrence of acute extrapyramidal symptoms (ie, drug-induced parkinsonism) on initial exposure to dopamine antagonist medications is associated with increased risk of developing TD in the future; reducing the dose of the dopamine antagonist medication greatly reduces risk for both drug-induced parkinsonism and TD. Masking drug-induced parkinsonism with anticholinergic medications, such as benztropine, does not reduce the risk of developing TD in the future

212 meeting modified Schooler-Kane criteria for TD vs 1098 with no item on AIMS rated higher than 1 and no history of TD.

PANSS = Positive and Negative Symptom Scale.

Many patients with TD are not aware they have it and will not seek treatment for it. However, TD is potentially stigmatizing and can impair social and behavioral functioning. Because TD can become irreversible, it is important to recognize and address it early.

Treatment with newly approved VMAT2 inhibitors has been shown to improve TD symptoms in randomized clinical trials.

To date, randomized, double-blind, placebo-controlled trials have shown that treatment with valbenazine or deutetrabenazine improves TD symptoms.

LS = least squares.

In the 6-week KINECT 3 trial, patients who received 80 mg valbenazine achieved significantly greater reductions in TD symptoms than patients who received placebo.

Collectively, these data indicate that the most common adverse effect is somnolence. Very few patients discontinued the trials because of adverse events (3% for valbenazine vs 2% for placebo).

In the 12-week AIM-TD trial, patients who received 36 or 24 mg/d deutetrabenazine achieved significantly greater reductions in TD symptoms than patients who received placebo.

Placebo-Controlled TD Studies: Adverse Reactions Reported in >= 2% of Patients Treated with Deutetrabenazine

A total of 4% of patients receiving deutetrabenazine required a dose reduction because of adverse reactions (vs 2% of patients taking placebo). Very few patients discontinued the trials because of adverse events (4% for deutetrabenazine vs 3% for placebo). ^aAll doses.

Number needed to harm vs placebo for discontinuation because of an adverse effect (AE) in the fixed-dose studies for either medication was ~100; thus likelihood to be helped or harmed for response vs discontinuation because of an AE is ~20.

There are important differences between the VMAT2 inhibitors.

• There is no need to discontinue or reduce or change antipsychotic therapy
• If patient is already on mood stabilizers and/or antidepressants – OK to continue therapy
• Both VMAT2 medications are effective in TD, regardless of the patient’s diagnosis (schizophrenia or mood disorder)
• Neither of the VMAT2-based FDA-approved medications destabilizes depression, mania, or psychosis; or induces suicidality¹

So which one should I use?

• There are no head-to-head studies of valbenazine and deutetrabenazine
• Customize therapy for patients in choosing medication
  • Consider adherence
  • Consider dosing regimen
  • Consider side-effect profile
• Tolerability and efficacy between the 2 medications may differ from patient to patient

Long-term data with VMAT2 inhibitors demonstrate sustained improvements in TD.

• Of the 163 participants in the KINECT 4 trial, 103 completed the long-term trial
• Sustained improvements were found in patients who received once-daily valbenazine, for both clinician- and patient-rated measures
• These improvements lasted until medication was discontinued at the end of the study
• No new safety signals or concerns emerged in this long-term study

• Of 343 patients enrolled in the deutetrabenazine extension study, 232 had previously received deutetrabenazine and 111 had previously received placebo
• The mean total daily dose of deutetrabenazine in the long-term study was 38.6 (1.13) mg
• Sustained improvements were found, using clinician-rated measures, until the end of the study
• No new safety signals or concerns emerged

Clinicians can take steps to improve coverage of VMAT2 inhibitors, including thorough documentation in prior authorization requests.

• Many, if not most, US insurance carriers cover VMAT2 therapy
• However, good documentation of need for VMAT2 therapy is critical to obtain their approval. The following must be included in preauthorization paperwork:
  • The location and severity of abnormal movements
  • That the patient has a diagnosis of TD
  • The bio-psychosocial impairment caused by TD
  • Why therapy with benztropine is inappropriate for this patient

Proactively document all 4 of the above. This reduces the chance of rejection of request for VMAT2 therapy.

• Both VMAT2 therapies have robust access/patient assistance programs

• Assume TD exists in your practice. It is still common and will continue to be because of increasing use of antipsychotic medications¹
• Screen with scheduled AIMS exams, especially in the older population¹
• Treat as quickly as possible after TD appears. Reliable, effective, and well-tolerated treatments are now available for persistent TD¹
• There are 2 FDA-approved treatments for TD: valbenazine and deutetrabenazine. Both are efficacious and tolerable.¹ They differ in
  • Frequency of administration (once daily for valbenazine vs twice daily for deutetrabenazine)
  • Titration (titrate to target dose of 80 mg/d for valbenazine vs dose to efficacy/tolerability for deutetrabenazine)
  • Need for food (administer deutetrabenazine with food)
  • Drug-drug interactions (consider CYP2D6 modulators for deutetrabenazine vs both CYP2D6 and CYP3A4 for valbenazine)
  • Contraindications (hepatic impairment for deutetrabenazine)¹
• However, the clinical usefulness of these treatments is rendered moot if TD goes unrecognized