Tardive Dyskinesia New approaches in diagnosis and treatment

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1 Tardive Dyskinesia New approaches in diagnosis and treatment Steven T. Szabo, MD, PhD Psychiatry and Behavioral Sciences Division of Translational Neuroscience Duke University Medical Center Durham, NC

2 Learning Objectives a. Define Tardive Dyskinesia as a psychiatric disorder per DSM-5 criteria b. Describe assessment of Tardive Dyskinesia c. Utilize current empirically-supported treatments for Tardive Dyskinesia

3 Current Practice Summary a) Screening patients for movement disorders on dopamine receptor blocking agents b) Using rating scales to objectively characterize symptom severity of Tardive Dyskinesia c) Choosing FDA-approved treatments for Tardive Dyskinesia

4 DSM-5 (TD Diagnosis) (G24.01) Tardive Dyskinesia Involuntary athetoid or choreiform movements (lasting at least a few weeks) generally of the tongue, lower face and jaw, and extremities Sometimes involving the pharyngeal, diaphragmatic, or trunk muscles) developing in association with the use of a neuroleptic medication for at least a few months. Symptoms may develop after a shorter period of medication use in older persons. In some patients, movements of this type may appear after discontinuation, or after change or reduction in dosage, of neuroleptic medications, in which case the condition is called neuroleptic withdrawalemergent dyskinesia. *Because withdrawal-emergent dyskinesia is usually time-limited, lasting less than 4-8 weeks, dyskinesia that persists beyond this window is considered to be tardive dyskinesia.

5 TD 39ekQ

6 Why do some get TD?: Etiology TD has been associated with genetic polymorphisms Dopamine receptor D2 (DRD2) gene Dopamine receptor D3 (DRD3) gene Dopamine transporter (DAT) gene Serotonin 2A and 2C receptor genes Manganese superoxide dismutase (MnSOD) gene Brain-derived neurotrophic factor (BDNF) gene * *Enhancement of BDNF may be protective against development of TD

7 Dopamine (DA) Compensatory supersensitivity of DA receptors in the striatum may develop after long-term blockade of D 2 receptors When dopamine D 2 -receptor blockade is reduced (even slightly), an exaggerated response of the postsynaptic dopamine D 2 -receptor (even to low concentrations of dopamine) may result Striatal disinhibition of the thalamocortical pathway from imbalance of D 1 and D 2 receptors may be involved Neurodegeneration secondary to lipid peroxidation or excitotoxic mechanisms may be responsible Although the dopamine D 2 receptor has traditionally been implicated in the pathogenesis of TD, there is mounting evidence to indicate that in some individuals, the dopamine D 3, D 4, and D 5 receptors are involved.

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9 Assessment Tools The most widely used instrument is the Abnormal Involuntary Movement Scale (AIMS) developed by the Psychopharmacology Research Branch of the National Institute of Mental Health (NIMH).

10 AIMS SCALE

11 Dopamine (DA) PD occurs sooner than TD TD occurs after months PD is loss of DA neurons in STN/DA receptor blockade TD is upregulation of DA receptors

12 Tetrabenazine, Clozapine, Treatments for TD

13 TD occurs in all ages. Who Does TD Target? Approximately 6 out of 100 individuals aged 7-21 years receiving DA antagonist treatment for 3 months had TD. Prevalence of TD is 29% in elderly patients receiving DA antagonist treatment for 3 months, and can be up to 67% in patients undergoing long-term treatment. Postmenopausal Women and African Americans appear to be especially vulnerable to TD after exposure to low doses of D2 blockers for short durations.

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15 Clinical Care for Patients and TD Fully inform the patient (or the legal surrogate if the patient is incompetent) of the possible courses of action. Discuss with the patient the advantages and disadvantages of dopamine antagonist treatment. A written treatment plan that documents agreement with the treatment course between the clinician and patient is helpful. Regularly review and revise the treatment plan as needed. If a patient exhibits a movement disorder when taking a drug, then gradual discontinuance of the causative drug generally is a wise course if the patient can tolerate a reduction in dose. Advise the patient to avoid receiving dopamine-receptor blocking drugs. Advise the patient to obtain a medical alert bracelet to warn against the administration of dopamine-receptor blocking drugs.

16 Medical-Legal Obligations?

17 Non-FDA Treatments with Variable Efficacy Clozapine Risperidone Olanzapine Calcium Channel Blockers Tiapride Vitamin E

18 Effects Of Vitamin E

19 Pathophysiology of TD

20 There are Two FDA Approved Treatments

21 Ingrezza Austedo

22 Mechanism of action of vesicular monoamine transporter 2 (VMAT2) inhibitors in tardive dyskinesia: reducing dopamine leads to less go and more stop from the motor striatum for robust therapeutic effects. Stephen Stall, 2018, CNS Spectrum, 23, p1-6.

23 Professional Practice Gaps a) Identify distinct movement disorders and Tardive Dyskinesia in at risk patients b) Choosing the appropriate treatment strategy for distinct movement disorders and Tardive Dyskinesia c) Personalizing treatment approaches in patients with Tardive Dyskinesia