Description

• Tardive dyskinesia (TD) is a neurologic condition resulting in delayed and persistent, abnormal, involuntary stereotypic movements of the tongue, lips, face, trunk, and extremities (1).
• Most commonly associated with long-term treatment with dopamine receptor antagonists (e.g., neuroleptic medications and metoclopramide)
• Movements can include grimacing, sticking out the tongue, and smacking and sucking the lips. According to the DSM-5, the spectrum of TD includes choreiform characteristics (i.e., rapid, jerky, or nonrepetitive), athetoid characteristics (i.e., slow, sinuous, continual), or rhythmic characteristics (1).
• TD symptoms can begin during treatment with neuroleptics or within 4 weeks of discontinuing neuroleptics. TD can be mild, moderate, or severe and is sometimes reversible.
• System(s) affected: nervous; musculoskeletal
• Synonym(s): orofacial dyskinesia

Epidemiology

TD rates for patients beginning treatment with conventional antipsychotics in their 5th decade or later are 3 to 5 times those found for younger patients, despite treatment with lower doses.

Incidence

• Predominant age: occurs in all ages; however, advanced age is a major risk factor for TD.
• Predominant sex: female > male (2)
• Patients taking 1st-generation antipsychotics: The cumulative incidence of TD was 5% after 1 year, 27% after 5 years, 43% after 10 years, and 52% after 15 years of exposure.
  • The cumulative incidence of persistent TD lasting for at least 3 months was 3% after 1 year, 20% after 5 years, and 34% after 10 years.
• Patients taking 2nd-generation antipsychotics: Studies have shown an annualized incidence rate between 2% and 3.9% (3).
• TD occurs in 20–40% of patients treated with neuroleptic drugs, with an incidence of 5% per year (2). The different manifestations of TD occur in varying frequency; for example, head and neck involvement (buccolingual or orofacial dyskinesias) are common, but only 1–2% treated with neuroleptics develop tardive dystonia.

Prevalence
Overall estimated prevalence of TD is 15–25% within 5 years of continuous classic antipsychotic use. Prevalence of TD with 2nd-generation antipsychotics recently found to be higher than previously thought. Meta-analysis composed of 41 studies from 2000 to 2015 revealed mean pooled TD rates of 30.0% with 1st-generation antipsychotics and 20.7% with 2nd-generation antipsychotics.

Etiology and Pathophysiology

Prolonged use of dopamine antagonist drugs

• Traditional antipsychotics
• Atypical antipsychotics
• Metoclopramide (Reglan), particularly in the elderly; prochlorperazine (Compazine), antiemetics with potent D₂ antagonism
• Antimalarials (chloroquine)
• Anti-Parkinson agents (bromocriptine, levodopa, and combined levodopa and carbidopa [Sinemet])
• Lithium
• Stimulants (amphetamine, methylphenidate, caffeine)
• Tricyclic antidepressants (less common than with antipsychotics)
• The mechanism by which TD occurs is still under debate. Hypotheses are as follows:
  • Antipsychotics (both traditional and atypical) have a high affinity for the D₂ receptors. It is postulated that the long-term blockade of these receptors leads to an upregulation in the number and sensitivity of D₂ receptors in the striated region of the brain (which controls muscle coordination). This upregulation is associated with involuntary movements and hence TD.
  • It also has been postulated that the depletion of γ-aminobutyric acid (GABA) in the substantia nigra may lead to orofacial dyskinesia.
  • Oxidative stress leading to neurotoxicity has been another proposed mechanism. The chronic blockage of dopamine receptors is hypothesized to cause an increased generation of hydrogen peroxide.
  • The most recent hypothesis is that chronic blockade of D₂ receptors and the consequent hypersensitization provoke maladaptive plasticity in corticostriatal transmission, leading to an imbalance between direct and indirect pathways (3).

Genetics

• No definitive data indicate a genetic basis for TD; however, recent research suggests a possible association with severe TD and polymorphic variants of the DRD3 receptor gene Ser9Gly, the serotonin 2A and 2C receptor genes, and genes related to GABAergic pathways (SLCA11, GABRB2) (3).
• Also, the absence of a glutathione S-transferase gene was associated with TD, particularly among Caucasian women.
• There have been associations with the polymorphism of the dopamine receptor D₂ gene, Taql A, and Taql B and associated haplotypes that may contribute to the development of TD.
• Some studies show that a poor metabolizer phenotype of CYP2D6 (an enzyme that metabolizes antipsychotic drugs) has greater risk of TD (2).

Risk Factors

• Use of 1st-generation antipsychotics (2)
  • Haloperidol (Haldol)
  • Chlorpromazine (Thorazine)
  • Fluphenazine (Permitil, Prolixin)
  • Thioridazine (Mellaril)
  • Perphenazine (Trilafon)
  • Trifluoperazine (Stelazine)
  • Pimozide (Orap)
  • Thiothixene (Navane)
  • Molindone (Moban)
  • Atypical antipsychotics have also been linked to TD, although in lower incidences than noted with the older medications. Examples of these medications include:
    • Quetiapine (Seroquel)
    • Olanzapine (Zyprexa)
    • Risperidone (Risperdal)
• Length of neuroleptic use
• Older age: the most significant risk factor (2)
• Postmenopausal women
• Mental retardation
• Smoking, alcoholism, and substance abuse
• Extrapyramidal symptoms (EPS) early in the course of neuroleptic treatment or a history of acute EPS (2)
• Presence of other movement disorders
• Diabetes mellitus
• Mood disorders (particularly major depressive disorder)
• Schizophrenia
• Female sex (2)

Geriatric Considerations
Occurs in all ages; however, advanced age is a major risk factor for TD.

General Prevention

• Choosing an atypical neuroleptic as first-line therapy might reduce the risk of developing TD (2).
• If traditional neuroleptics must be used, limit long-term use and use the lowest effective doses.
• Continuous use of metoclopramide should be limited to <12 weeks.
• It is important that, prior to use, the risk and benefits be discussed with the patients. Informed consent should be obtained. Once started, monitor symptoms periodically.

Commonly Associated Conditions

• Presence of movement disorder
• Psychiatric disorders commonly treated with neuroleptics