What are the causes of tardive dyskinesia?

From the Guidelines

Tardive dyskinesia is primarily caused by long-term use of dopamine receptor blocking medications, particularly antipsychotics like haloperidol, chlorpromazine, risperidone, and olanzapine, as well as certain antiemetics such as metoclopramide and prochlorperazine. The condition typically develops after months or years of medication use, though it can occasionally appear after shorter periods or even after discontinuation of the medication 1. Older adults, females, and those with mood disorders or diabetes have a higher risk of developing tardive dyskinesia.

Causes and Risk Factors

The mechanism involves hypersensitivity of dopamine receptors in the basal ganglia following chronic blockade, leading to an imbalance in the nigrostriatal pathway when medication is reduced or stopped 1. This results in involuntary, repetitive movements typically affecting the face, mouth, and tongue, but sometimes involving the trunk and extremities.

• Long-term use of antipsychotics is a major risk factor, with typical antipsychotics like haloperidol carrying a higher risk compared to atypical antipsychotics like risperidone and olanzapine 1.
• Certain antiemetics, such as metoclopramide and prochlorperazine, can also cause tardive dyskinesia due to their dopamine receptor blocking properties.
• Older adults, females, and individuals with mood disorders or diabetes are at a higher risk of developing tardive dyskinesia.

Prevention and Management

Prevention involves using the lowest effective dose of antipsychotics, preferring atypical over typical antipsychotics when possible, and regular monitoring for early signs of movement disorders 1.

• Regular assessment for dyskinesias should occur at least every 3 to 6 months, using tools like the Abnormal Involuntary Movement Scale 1.
• If tardive dyskinesia occurs, attempts should be made to either lower the dose or switch to another medication, most likely an atypical antipsychotic 1.

From the FDA Drug Label

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including quetiapine Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment

The causes of tardive dyskinesia are:

• Antipsychotic drug treatment: The use of antipsychotic drugs, including quetiapine, haloperidol, and chlorpromazine, is associated with the development of tardive dyskinesia.
• Duration and cumulative dose of treatment: The risk of developing tardive dyskinesia increases with the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient.
• Unknown factors: The exact causes of tardive dyskinesia are not fully understood, and it is impossible to predict which patients will develop the syndrome at the start of antipsychotic treatment 2, 3, 4.

From the Research

Causes of Tardive Dyskinesia

The causes of tardive dyskinesia (TD) are associated with the use of certain medications, particularly those with dopamine antagonism, such as antipsychotics 5, 6. The following are some key points related to the causes of TD:

• TD is a potentially permanent movement disorder resulting from chronic use of dopamine receptor blocking agents (DRBA) 6.
• Identified risk factors include the type of antipsychotic agent, duration of illness, cumulative dose of DRBA, advanced age, female sex, and African and Caucasian ethnicity 6.
• Genetics may play a role in the development of TD, with susceptibility gene candidates including those involved in DRBA metabolism and the targets or receptors of DRBA's 6.
• The pathogenesis of TD is unknown, but three main theories have been proposed: dopamine receptor supersensitivity, oxidative stress, and maladaptive synaptic plasticity 6, 7.

Medication-Related Causes

The use of certain medications, particularly antipsychotics, is a major cause of TD. The following points highlight the relationship between medications and TD:

• All antipsychotics, including atypical antipsychotics (AAPs), may cause TD 7.
• The risk of TD is lower with AAPs than with typical antipsychotics (TAPs), but remains a problem due to the increasing prescription of AAPs 7.
• Important risk factors associated with TD include the duration of antipsychotic use, age, and ethnicity other than Caucasian 7.

Other Potential Causes

While the exact causes of TD are still unknown, research suggests that other factors may contribute to its development. These include:

• Dopamine receptor supersensitivity resulting from chronic dopamine receptor blockade 6, 7.
• Oxidative stress and maladaptive synaptic plasticity 6, 7.
• Genetic factors, including variations in genes involved in DRBA metabolism and neurotransmitter packaging 6.