Causes and Risk Factors of Tardive Dyskinesia

Tardive dyskinesia may occur as a side effect of taking neuroleptic drugs (also described as antipsychotic medications) and certain other medicines.

The medications that can cause tardive dyskinesia are indicated as treatments for schizophrenia, other types of psychosis, depression, bipolar disorder, epilepsy, and certain gastrointestinal conditions.

It is estimated that approximately 25.3% of people who use antipsychotics experience tardive dyskinesia as a side effect.

Common Causes

The medications that can cause tardive dyskinesia modify neurotransmitter activity in the brain, especially dopamine and serotonin.

Neuroleptics reduce the effects of dopamine in the brain, which is believed to play a role in their therapeutic effects, as well as in the development of tardive dyskinesia. Neuroleptics and antidepressants also alter serotonin activity, but this has not been closely linked to tardive dyskinesia.

Antipsychotics cause tardive dyskinesia more often than other drug types. Generally, first-generation, older antipsychotics have been considered more likely to cause tardive dyskinesia than newer second-generation antipsychotics, which are also called atypical antipsychotics.

However, while the side effect is not as common with second-generation antipsychotics as it is with first-generation antipsychotics, there is a risk of tardive dyskinesia with second-generation antipsychotics as well.

Some of the medications that can cause tardive dyskinesia include: 

• First-generation antipsychotics: Chlorpromazine, fluphenazine, haloperidol, perphenazine, prochlorperazine, thioridazine, trifluoperazine
• Second-generation antipsychotics: Risperdal (risperidone) and Invega (paliperidone)
• Antidepressants: Fluoxetine, trazodone, doxepin, clomipramine, and amitriptyline
• Anti-epileptic drugs (AEDs): Phenytoin, carbamazepine, and lamotrigine
• Anticholinergics: Cogentin (benzatropine) and trihexyphenidyl (used to treat Parkinson’s disease; may help reduce symptoms of tardive dyskinesia, but may also cause or worsen the symptoms in some situations)
• Antiemetics (anti-nausea medications): Reglan (metoclopramide) and Compazine (prochlorperazine), used to treat nausea, gastric motility problems, and gastroesophageal reflux disease (GERD). The incidence of tardive dyskinesia with these medications is relatively low. For example, this side effect is estimated to affect less than 1% of people who use metoclopramide, and it is usually associated with higher doses and longer durations of treatment.

The medications that can cause tardive dyskinesia are also used off-label for a variety of conditions. For example, antipsychotics are sometimes used in the treatment regimen for mood disorders, and AEDs—also called anticonvulsants—are sometimes used in the management of chronic pain conditions.

Metoclopramide and prochlorperazine are sometimes used to treat acute migraine episodes, especially when nausea is a major symptom of the episode or during pregnancy.

Pathophysiology 

Tardive dyskinesia is characterized by intermittent, abnormal involuntary movements involving the face, mouth, tongue, or extremities. These movements are believed to be associated with dysfunction of dopamine activity in the basal ganglia, a region of the brain that mediates voluntary movements.

This side effect can be temporary and may improve after discontinuation of the medication, or it can be permanent and may last long after the medication is stopped. Medications that cause tardive dyskinesia may temporarily or permanently alter neurotransmitter activity or may damage structures of the basal ganglia.

Changes that have been noted with tardive dyskinesia include:

• Neuroleptics are intended to reduce the amount of dopamine or the action of dopamine on its receptors. It is believed that chronically inhibiting the action of dopamine could make the dopamine receptors hypersensitive to stimulation and that this could contribute to symptoms of tardive dyskinesia. 
• Tardive dyskinesia has been associated with changes in gamma-aminobutyric acid (GABA) activity and modification of the activity of sodium channels, which are part of the actions of AEDs.
• It has been proposed that medication-induced oxidative damage in the brain could play a role in the development of tardive dyskinesia.

Genetics

Anyone who takes a neuroleptic can develop tardive dyskinesia. However, not everyone who uses a neuroleptic will develop the condition, and some populations are more prone to the side effect than others. 

A higher likelihood of tardive dyskinesia is associated with:

• Advanced age 
• Female
• White or of African descent 
• Intellectual disability
• Brain damage
• Mood disorders
• Negative symptoms of schizophrenia (can include diminished speech, decreased emotions, reduced emotional expression, social withdrawal)

These factors may have a genetic component, and there may be a higher tendency to experience tardive dyskinesia among people who have family members who also have the side effect. Additionally, certain genes have been associated with a higher predisposition to tardive dyskinesia.

Genes that have been linked to a potentially increased risk of developing tardive dyskinesia include:

• Genes that affect the action of cytochrome P450, which is involved with the metabolism of antipsychotics
• Genes that affect the production of dopamine D2 and D3 receptors
• Genes involved in serotonin 2A and 2C receptor function
• Genes that direct production of vesicular monoamine transporter 2 (VMAT 2), an enzyme that mediates neurotransmitter packaging
• The gene for manganese superoxide dismutase (MnSOD), an antioxidant enzyme
• The heparan sulfate proteoglycan 2 (HSPG 2) gene

Alterations in these genes have been associated with tardive dyskinesia, but research about the genetics and heredity of the condition has yet to reveal more definitive links. 

Clinical and Lifestyle Risk Factors

Some risk factors can increase the likelihood of developing tardive dyskinesia.

Having a psychotic illness for a long time and/or taking a neuroleptic for a long time are independent risk factors. Additionally, taking multiple neuroleptics at a time or having high levels of antipsychotic drugs in the blood can increase the risk of this side effect. 

Having other movement-related side effects caused by an antipsychotic, especially soon after starting the medication, is also associated with tardive dyskinesia. 

Side effects often associated with tardive dyskinesia include parkinsonism (symptoms similar to those of Parkinson’s disease) and akathisia (a type of persistent physical and mental restlessness and distress).

Other risk factors include diabetes, smoking, and alcohol and substance abuse.

A Word From Verywell

If you are taking a neuroleptic for a psychiatric condition or taking another medication associated with tardive dyskinesia, such as for a gastrointestinal condition, the medicine can be highly effective for controlling your symptoms. However, you can develop side effects, including tardive dyskinesia.

It is important that you learn how to recognize symptoms of tardive dyskinesia so that you can talk to your healthcare provider about them as soon as they start to develop. But you should also keep in mind that most people can take antipsychotic medications for many years without ever experiencing tardive dyskinesia as a side effect.