Answers To Your Questions About Tardive Dyskinesia An Educational Webinar Series for Patients and Families/Caregivers Part 3: If I Already Have Tardive Dyskinesia, What Now?

Faculty Presented by: Leslie Citrome, MD, MPH Clinical Professor of Psychiatry and Behavioral Sciences New York Medical College, Valhalla, NY Supported by an educational grant from Teva Pharmaceuticals Prepared by Delaware Media Group for TDAnswers.com

Introduction In the first two webinars we discussed: What causes tardive dyskinesia, The common symptoms and risk factors, Some ways to prevent or minimize this condition. In this webinar we will talk about methods that can be used to treat TD once it has started.

Brief Review of TD Definition: Tardive dyskinesia (TD) refers to uncontrollable abnormal movements (often in the areas of the face and hands) that result from taking certain medications Symptoms: TD usually begins with spontaneous, involuntary movements of the face, mouth, lips and tongue Causes: TD is usually caused by long-term exposure to certain types of drugs, such as antipsychotics, which are used to treat mental disorders (Actor portrayal)

Is TD Reversible? Until recently, TD was considered irreversible Discontinuing the drug (antipsychotic) may be one way to slow or limit TD Many people cannot altogether stop the antipsychotic. These patients have a vital need for treatment of their underlying psychiatric disorder

Switch from a first-generation to a second-generation antipsychotic Is TD Reversible? Some people may be switched to a lower dose, or to a different antipsychotic Switch from a first-generation to a second-generation antipsychotic After a switch, temporary increase in abnormal movements (withdrawal dyskinesia) may occur. Over time, TD symptoms may abate Switch from second-generation antipsychotic to a different second-generation agent such as clozapine

Overview of Approaches Used to Treat TD Modify current drug treatment Switch to second-generation antipsychotic Use a lower dose Discontinue drug if possible (not always possible) Medications to treat TD (strong evidence supporting use)   Valbenazine (Ingrezza®) FDA approved for TD Deutetrabenazine (Austedo®) Approved for other conditions (Huntington’s disease) Currently being studied for TD, under review by FDA Alternative treatments (weaker evidence supporting use) Clonazepam (short-term use only) Ginkgo biloba (dietary supplement) Amantadine (antiviral agent)

Overview of Approaches Used to Treat TD Tested and NOT recommended Diltiazem (calcium channel blocker) Galantamine (drug used for Alzheimer’s disease) Eicosapentaenoic acid (Omega 3 fatty acid) Insufficient or inadequate testing to make any definite  recommendations Acetazolamide, bromocriptine, thiamine, baclofen, vitamin E, vitamin B6, selegiline, melatonin, nifedipine, levetiracetam, buspirone, yi-gan san, biperiden discontinuation, botulinum toxin type A, electroconvulsive therapy, alpha-methyldopa, reserpine, pallidal, deep brain stimulation

Modify Current Drug Treatment Switch to second-generation antipsychotic Lower dose of second- generation antipsychotic Discontinue drug or switch to different class (if possible) For example, use an antipsychotic to treat acute episode of mood disorder, then change to a different medications for longer-term management First-Generation Second-Generation Chlorpromazine (Thorazine®) Fluphenazine (Prolixin®) Haloperidol (Haldol®) Loxapine (Loxitane®) Perphenazine (Trilafon®) Thiothixene (Navane®) Trifluoperazine (Stelazine®)   Asenapine (Saphris®) Aripiprazole (Abilify®) Brexpiprazole (Rexulti®) Cariprazine (Vraylar®) Clozapine (Clozaril®) Iloperidone (Fanapt®) Lurasidone (Latuda®) Olanzapine (Zyprexa®) Paliperidone (Invega®) Quetiapine (Seroquel®) Risperidone (Risperdal®) Ziprasidone (Geodon®)

Medications for TD: VMAT-2 Inhibitors How Do VMAT-2 Inhibitors Work? Dopamine is a neurotransmitter, a chemical used by brain cells to communicate with each other TD is most likely caused by irregular dopamine signalling in the brain VMAT-2 inhibitors are thought to reduce these irregular signals  Valbenazine (Ingrezza®) Approved by FDA in April 2017 for adults with TD Deutetrabenazine (Austedo®) Approved by FDA for abnormal movements (chorea) due to Huntington’s disease Currently in clinical studies for TD

How Well Do These Medications Work to Control TD? Valbenazine Clinical trials of people with moderate to severe TD Participants had schizophrenia, schizoaffective disorder, or mood disorder On average, uncontrollable movements were reduced by about 30% within 6 weeks of taking valbenazine. In some people, improvements occurred as early as 2 weeks After 1 year, many patients continued to have improved symptoms Few patients stopped taking valbenazine due to side effects of this drug Many patients were able to remain on their antipsychotic drug Longer trials are needed

How Well Do These Medications Work to Control TD? Deutetrabenazine Deutetrabenazine has been used to treat uncontrollable movements (chorea) in people with Huntington's disease. This agent is being evaluated by the FDA for the treatment of TD   Recent study in TD: ARM-TD Trial (Aim to Reduce Movements in Tardive Dyskinesia) 12-week trial of patients with moderate to severe TD Patients who responded had an average 3-point change in TD severity score Longer-term trial (1 year) is under way

Precautions For Use of VMAT-2 Inhibitors People who take VMAT-2 inhibitors should be aware of possible side effects and drug interactions Drowsiness (somnolence) is the most common side effect Substances that act on cytochrome P450 (CYP) pathways may affect the amount of the drug in the body. Certain drug categories should be avoided. These should be discussed with a doctor or pharmacist. They include: The safety of VMAT-2 inhibitors has not been studied in pregnant women or in children. Monoamine oxidase inhibitors (MAOI), which are used to treat depression, Parkinson’s disease, and other conditions. A few examples are selegiline (Eldepryl®) and rasagiline (Azilect®).

Tetrabenazine Tetrabenazine is an older drug in the VMAT-2 category, also approved for Huntington’s chorea It needs to be taken more often during the day, and may be associated with adverse effects such as depression 

Importance of Monitoring and Early Detection of TD The patient’s need for antipsychotic treatment should be evaluated regularly Patient should be examined regularly by a professional for signs of TD Patients receiving first-generation antipsychotics should be tested for TD every 6 months Patients receiving second-generation antipsychotics should be tested for TD once a year More frequent evaluation for TD is suggested for people with higher risks

For Caregivers: Supporting the Person with TD Person with TD may not be aware of his/her symptoms Caregivers should discuss abnormal movements with the patient’s medical professionals Many organizations can provide additional information and support for people with TD and families/caregivers National Alliance on Mental Illness (NAMI) National Organization for Rare Disorders (NORD)

Summary The availability of new treatments and others currently under development is a hopeful sign for those suffering from this long-neglected condition.  

Conclusion You have just completed Part 3 in a series on tardive dyskinesia (TD), focusing on treatment options. To learn more about TD, see Webinars 1 and 2 in this series: Part 1. What is TD? [LINK] Part 2. Can TD be Prevented? [LINK]

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