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- 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
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.
- 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% (1).
- 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.
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.
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])
- 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 (1).
- 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) (1).
- 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).
- 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
- 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 (3)
- Female sex (2)
Occurs in all ages; however, advanced age is a major risk factor for TD.
- 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