Webinar

Webinar: Assessing & Diagnosing Tardive Dyskinesia and Introducing Ingrezza

Genoa Healthcare and Neurocrine June 21, 2018

The first part of our two-part webinar series, Assessing & Diagnosing Tardive Dyskinesia (TD), presented by Dr. Joseph McEvoy, defined and differentiated TD from other drug-induced movement disorders.

Recording link: https://engage.vevent.com/rt/ingrezza~odwebcast7

Here are some key takeaways:

  • Tardive Dyskinesia is defined as “involuntary athetoid or choreiform movements (lasting at least a few weeks) generally of the tongue, lower face and jaw, and extremities (but sometimes involving the pharyngeal, diaphragmatic, or trunk muscles) developing in association with the use of neuroleptic medication for at least a few months”
  • Symptoms typically include:
    • Increased blinking and mouth movement
    • Lip protrusion and pursing
    • Head nodding
    • Hand and finger flicking
    • An involuntary protrusion of the tongue
  • These symptoms develop in response to long term usage of dopamine receptor blocking agents (DRBAs) like:
    • Antipsychotics, some antidepressants and antiemetic medications, and the mood stabilizer lithium.
  • In addition to the consumption of TD-triggering medications, additional patient risk factors for the condition include:
    • Increased age, current substance abuse, a comorbid mood disorder diagnosis, as well as (for women) being post-menopausal.

What Makes TD Different from Other Movement Disorders?

  • TD can be confused with other extrapyramidal symptoms caused by the consumption of certain medications such as:
    • Acute dystonia, which includes severe, abrupt spasms of the head, jaw, or arms, and is seen within hours to days of antipsychotic use
    • Acute akathisia, characterized by motor restlessness, also seen within hours to days of antipsychotic use
    • Acute parkinsonism, which can present as a tremor or as an extreme slowness of movement in a patient, often with an absence of facial expression and a droning voice. Symptoms develop within weeks of beginning an antipsychotic.

How to screen for it:

  • Allow patients adequate time to get relaxed and comfortable. If possible, observe them walking. While walking and while at rest, TD symptoms are more likely to show.
  • Utilize ground staff observations to inform your clinical opinions as well:
    • Ask those who spend time with the patient in person to report on abnormal movements.
    • As a patient walks into the office, note any movements of his or her face, mouth, hands, and arms.
    • Have ground staff pay attention to the patient’s gait as they enter or leave the room.

Here are a few other tips to help tease out TD symptoms:

  • Ask the patient to remove any gum or candy from his or her mouth. Be sure to clarify whether a client wears dentures or has other teeth or oral problems.
  • Ask the patient to remove his or her socks and shoes so that you can examine their toes and feet.
  • Ask the patient to perform one or more activation maneuvers, such as:
    • Holding their hands straight out in front of them
    • Letting their hands hang while standing or sitting in a chair
    • Saying five words beginning with the letter “T”
    • Holding their mouth open while having them touch each finger to their thumb
    • Asking them to open their mouth for a while to observe their tongue or asking them to stick out their tongue.
    • Asking them to stand, turn right or left, or walk to the edge of the room.
    • You can also request that the patient sit in a chair without arm rests, as arm rests can mask the limb movements associated with TD.

Treatments

  • It is not recommended to use:
    • Benztropine as this drug can exacerbate the symptoms of TD.
    • Anticholinergics, which have the potential to worsen TD features.

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The second half of our webinar series is: Introducing INGREZZA: The First FDA-Approved Treatment for Adults with Tardive Dyskinesia.

Recording link: https://engage.vevent.com/rt/ingrezza~webcast

Key takeaways:

  • Ingrezza is the first FDA-approved medication for Tardive Dyskinesia
  • The usage of antipsychotics has increased 4X in last 23 years (5 million patients); >500,000 patients may have TD
  • Factors associated with increased risk for TD:
    • Treatment factors:
      • Cumulative exposure to antipsychotics
      • Treatment with anticholinergics
      • History of extrapyramidal side effects
      • Potency of DRBA
    • Patient factors:
      • Increased age
      • Current substance abuse
      • DIagnosis of mood disorder

Ingrezza Mechanism of Action:

  • Ingrezza (valbenazine)
    • The exact mechanism of action is unknown, but it is thought that valbenazine works via reversible inhibition of VMAT2, a vesicular monoamine transporter
    • VMAT2 (Vesicular Monoamine Transporter 2) is a transporter that regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release
    • Antipsychotics are dopamine receptor blocking agents (DRBA’s). Dopamine receptors are blocked chronically, leading to upregulation in creation of dopamine receptors → leads to hypersensitivity to dopamine due to the excess number of dopamine receptors on the postsynaptic neuron
    • Ingrezza exhibits high affinity for VMAT2 which regulates dopamine output by inhibiting dopamine uptake from the cytoplasm into the synaptic vesicles, thereby inhibiting the accumulation of dopamine into the presynaptic neuron.
    • D2 receptors can be upregulated after prolonged exposure to antipsychotics
    • Ingrezza reduces the number of dopamine molecules that go into vehicles presynaptic, when dopamine neurons fire up, releasing less dopamine
  • Key inclusion criteria:
    • Age 18 to 85
    • Schizophrenia, schizoaffective disorder or mood disorder
    • Moderate or severe TD
    • Stable dose of maintenance medications for psychiatric conditions
    • Clinically stable medical conditions
  • Key exclusion criteria:
    • BPRS total score of >50 at screening
    • Significant suicidal ideation or behavior
    • History of long QT syndrome
    • For participants with schizophrenia or schizoaffective disorder:
      • CDSS total score of >10
      • PANNS total score of >70
    • With mood disorder:
      • YMRS total score of >10
      • MADRS total score of >13
      • Hospitalization for BD or MDD within 6 months before screening
      • Mood episodes within 2 months before screening
      • History of rapid or ultra-rapid cycling

Clinical studies of Ingrezza:

  • 6-week double blind, placebo-controlled Ingrezza treatment:
    • Average age: 60, age at TD diagnosis: 49
    • ½ of participants male
    • White: 57%, African American; 38%
    • 2/3rd of participants had schizophrenia or schizoaffective disorder, and 34% had mood disorder
    • Most were taking antipsychotic medications
      • Mostly second-generation antipsychotics, also antidepressants, antiepileptics, anxiolytics, and anticholinergics
  • Percent of participants with AIMS score reduced >50% at week 6
    • Ingrezza 80 mg once daily: 40%
    • Ingrezza 40 mg once daily: 24%
    • Placebo: 9%
  • Ingrezza can cause somnolence
  • Kinect 3: Long-term extension period data of 52 weeks (beyond 6 weeks of treatment)
    • 8 weeks: More reduction in AIMS for both 40 and 80 mg, and fairly sustained until 48 weeks
    • Placebo group: Went to 40mg and 80mg daily, in 6-8 week fashion; had same drop in AIMS score
    • After 48 weeks, participants stopped taking Ingrezza. As soon as it was out of system, increase in AIMS score went back to baseline score

Warnings, Reactions, & Drug Interactions:

    • Might prolong QT interval
    • Should be avoided in patients with congenital long QT syndrome or arrhythmias
  • Adverse reactions
    • General disorders: somnolence (fatigue, sedation)
    • Nervous system disorders (anticholinergic effects, balance disorders, headache, akathisia)
    • Gastrointestinal disorders (vomiting, nausea)
    • Musculoskeletal disorders (arthralgia)
    • 3% with active treatment had to stop because adverse effect, 2% from placebo
  • Drug interactions:
    • MAOIs
    • Strong CYPEA4 Inhibitors
    • Strong CYP2D6 Inhibitors
    • Strong CYP3A4 Inducers
    • Digoxin