Treatment of Patients With Schizophrenia: Tardive Dyskinesia

Last updated March 15, 2022

Introduction

Introduction

  • This pocket guide includes selected statements from the American Psychiatric Association Practice Guideline for the Treatment of Patients with Schizophrenia, 3rd edition, related to the assessment and treatment of tardive dyskinesia.
  • Individuals with tardive dyskinesia, as with any individual with schizophrenia, should be treated in the context of a person-centered treatment plan that includes evidence-based non-pharmacological and pharmacological treatments.
  • Tardive syndromes can occur after exposure to any antipsychotic medication. In adult patients treated with first-generation antipsychotic agents, tardive dyskinesia occurs at a rate of approximately 4%-8% per year, which is about three times the annual risk with second generation antipsychotic agents.
  • Various factors are associated with greater vulnerability to tardive dyskinesia. Patients at increased risk for developing abnormal involuntary movements include individuals older than 55 years; women; individuals with a mood disorder, substance use disorder, intellectual disability, or central nervous system injury; individuals with high cumulative exposure to antipsychotic medications, particularly high potency dopamine D2 receptor antagonists; and patients who experience acute dystonic reactions, clinically significant parkinsonism, or akathisia. Abnormal involuntary movements can also emerge or worsen with antipsychotic cessation.
  • Please visit the full text guideline here for detailed recommendations on the treatment of schizophrenia as well as detailed information on pharmacology, side effects, and dosing information of antipsychotic medications and VMAT2 inhibitors.

Assessment

Assessment

  • Tardive syndromes are persistent abnormal involuntary movement disorders caused by sustained exposure to antipsychotic medication, the most common of which are tardive dyskinesia, tardive dystonia, and tardive akathisia.
  • They begin later in treatment than acute dystonia, akathisia, or medication-induced parkinsonism and they persist and may even increase, despite reduction in dose or discontinuation of the antipsychotic medication.
  • Typically, tardive dyskinesia presents 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)".
  • Tardive dystonia and tardive akathisia resemble their acute counterparts in phenomenology.
  • Regular assessment of patients for tardive syndromes through clinical examination or through the use of a structured evaluative tool can aid in identifying tardive syndromes, clarifying their likely etiology, monitoring their longitudinal course, and determining the effects of medication changes or treatments for tardive dyskinesia.
    • Patients, family members, and other persons of support may be able to provide information about the onset of movements; their longitudinal course in relation to treatment or other precipitants; and their impact on functioning, health status (including dentition), and quality of life.
  • Clinical assessment of akathisia, dystonia, parkinsonism, and other abnormal involuntary movements, including tardive dyskinesia, should be performed at each visit.
  • Assessment with a structured instrument (e.g., AIMS, DISCUS) should be performed at a minimum of every 6 months in patients at high risk of tardive dyskinesia and at least every 12 months in other patients as well as if a new onset or exacerbation of preexisting movements is detected at any visit.
    • When using scales such as the AIMS or the DISCUS, it should be noted that there is no specific score threshold that suggests a need for intervention although ranges of scores are noted to correspond with mild, moderate, and severe symptoms.
    • In addition, the same total score can be associated with significantly different clinical manifestations and varying impacts on the patient.

Treatment

Treatment

APA recommends that patients who have moderate to severe or disabling tardive dyskinesia associated with antipsychotic therapy be treated with a reversible inhibitor of the vesicular monoamine transporter2 (VMAT2). (1B)
  • If no contributing etiology is identified and moderate to severe or disabling tardive dyskinesia persists, treatment is recommended with a reversible inhibitor of VMAT2. Treatment with a VMAT2 inhibitor can also be considered for patients with mild tardive dyskinesia based on factors such as patient preference, associated impairment, or effect on psychosocial functioning. See Table for characteristics of VMAT2 inhibitors that are currently available in the U.S.
  • Deutetrabenazine or valbenazine are preferred over tetrabenazine because of the greater evidence base supporting their use. Tetrabenazine has a shorter half-life and greater rates of associated depression when used in the treatment of patients with Huntington’s disease.
  • Other factors that may influence choice of a VMAT2 inhibitor relate to hepatic or renal function – tetrabenazine and deutetrabenazine are contraindicated in individuals with hepatic impairment whereas valbenazine is not recommended for use in individuals with severe renal impairment.

Benefits

In individuals with moderate to severe or disabling tardive dyskinesia associated with antipsychotic therapy, VMAT2 inhibitors can be associated with significant reductions in motor signs and symptoms of tardive dyskinesia. These medications may also be effective in other tardive syndromes.

Harms

The harms of treatment with VMAT2 inhibitors include sedation and, with tetrabenazine, extrapyramidal effects, akathisia, insomnia, anxiety, nausea, and falls. Depression and suicidal ideas have been reported in individuals who were administered VMAT2 inhibitors for treatment of Huntington's disease. Such effects are possible in individuals treated for tardive dyskinesia although they were not reported in clinical trials.

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as far outweighing the potential harms. The majority of individuals with moderate to severe or disabling tardive dyskinesia would have a greater likelihood of experiencing benefits of a VMAT2 inhibitor than experiencing harms. Patient preferences to reduce motor signs and symptoms are also likely to favor treatment.

Patient Preferences

Clinical experience suggests that most patients with moderate to severe or disabling tardive dyskinesia wish to have a diminution of their motor signs and symptoms. Most patients would be willing to take medication to achieve a reduction in motor signs and symptoms, particularly if it was well tolerated.

Reversible inhibitors of human vesicular monoamine transporter type 2a

Generic name
Trade name
Deutetrabenazine
Austedo
Tetrabenazine
Xenazine
Valbenazine
Ingrezza
Available formulations (mg) Tablet: 6, 9, 12 Tablet: 12.5, 25 Capsule: 40, 80
Typical dose range (mg/day) 12–48 25–75 40–80
Bioavailability 80% 75% 49%
Time to peak level (hours) 3–4 1–2 0.5–1
Protein binding 60% to 68%
  (alpha-HTBZ)
59% to 63%
  (beta-HTBZ)
82% to 85%
60% to 68%
  (alpha-HTBZ)
59% to 63%
  (beta-HTBZ)
>99% 64% alpha-HTBZ
Metabolism Hepatic Hepatic Hepatic
Metabolic enzymes/transporters Major substrate of CYP2D6b, minor substrate of CYP1A2 and CYP3A4 Major substrate of CYP2D6c Major substrate of CYP3A4, minor substrate of CYP2D6d
Metabolites Deuterated alpha- and beta-HTBZ: Active Alpha-, beta-, and O-dealkylated HTBZ: Active alpha-HTBZ: Active
Elimination half-life (hours) Deuterated alpha- and beta-HTBZ: 9–10 Alpha-HTBZ: 4–8
Beta-HTBZ: 2–4
15–22
Excretion Urine (~75%-85% changed); feces (~8%–11%) Urine (~75% changed); feces (~7%–16%) Urine: 60%; feces: 30%
Hepatic impairment Contraindicated Contraindicated Maximum dose of 40 mg daily with moderate to severe impairment (Child-Pugh score 7–15)
Renal impairment No information available No information available Use not recommended in severe renal impairment (CrCl <30 mL/min)
Common adverse effect Sedation Sedation, depression, extrapyramidal effects, insomnia, akathisia, anxiety, nausea, falls Sedation
Effect of food on bioavailability Food affects maximal concentration. Administer with food. Unaffected by food Can be taken with or without food. High fat meals decrease the Cmax and AUC for valbenazine, but values for the active metabolite (alpha-HTBZ) are unchanged.
Commentse Swallow tablets whole and do not chew, crush, or break. Give in divided doses; increase from initial dose of 12 mg/day by 6 mg/week to maximum dose of 48 mg/day. Retitrate dose for treatment interruptions of more than 1 week.f Give in divided doses; increase from initial dose of 25–50 mg/day by 12.5 mg/week to maximum of 150–200 mg/day. Retitrate dose for treatment interruptions of more than 5 days.f Initiate at 40 mg/day and increase to 80 mg/day after 1 week. Continuation of 40 mg/day may be considered for some patients.f
a This table includes information compiled from multiple sources. Detailed information on issues such as dose regimen, dose adjustments, medication administration procedures, handling precautions, and storage can be found in product labeling. It is recommended that readers consult product labeling information for authoritative information on these medications.
b Do not exceed total daily dosage of 36 mg/day (18 mg/dose) in poor CYP2D6 metabolizers or patients taking a strong CYP2D6 inhibitor. Assess ECG before and after increasing the daily dose above 24 mg in patients at risk for QTc prolongation.
c Test for CYP2D6 metabolizer status before giving doses >50 mg/day. Do not exceed 50 mg/day in poor metabolizers or in patients treated with a strong inhibitor of CYP2D6.
d Use is not recommended with strong CYP3A4 inducer. A reduced dose is recommended with concomitant use of strong CYP3A4 or CYP2D6 inhibitors or in poor CYP2D6 metabolizers.
e All VMAT2 inhibitors are contraindicated within 2 weeks of a monoamine oxidase inhibitor, within 20 days of reserpine, or in patients with active suicidal ideas or untreated depression. Tetrabenazine and deutetrabenazine carry a boxed warning related to depression and suicidal ideation in patients with Huntington’s disease.
f Avoid use in patients with congenital long QT syndrome, with arrhythmias associated with a prolonged QT interval, or with other risks for QTc prolongation, such as interactions via CYP metabolism.

Recommendation Grading

Disclaimer

This pocket guide attempts to define principles of practice that should produce high-quality patient care. It is applicable to specialists, primary care, and providers at all levels. This pocket guide should not be considered exclusive of other methods of care reasonably directed at obtaining the same results. The ultimate judgment concerning the propriety of any course of conduct must be made by the clinician after consideration of each individual patient situation. Neither IGC, the medical associations, nor the authors endorse any product or service associated with the distributor of this clinical reference tool.