Assessing Tardive Dyskinesia Risk

Any patient on a dopamine receptor-blocking medication may develop tardive dyskinesia (TD), though most often the condition is associated with antipsychotic medications.

“You would be ill-advised to think that everyone isn’t potentially vulnerable,” John Lauriello, MD, of Thomas Jefferson University in Philadelphia, told MedPage Today.

“The truth is that you don’t know who you give an antipsychotic to might get TD,” he continued. “You have to be cautious with every single person you take care of.”

Certain risk factors and drugs may raise a patient’s susceptibility for TD beyond average.

Patient Variables

Older age and female sex are both TD risk factors, noted Hengameh Zahed, MD, PhD, of Stanford Medicine in Palo Alto, California.

People over age 40 carry a higher risk, and that risk increases after age 65 due to age-related brain changes. Females tend to develop TD at higher rates, with postmenopausal women having rates as high as 30% after 1 year of antipsychotic exposure.

“Literature has suggested that elderly patients may be at a 3.2-fold higher risk of developing medication-induced tardive dyskinesia,” said Mustafa Mufti, MD, of ChristianaCare Health System in Wilmington, Delaware.

Race is another variable: studies have shown that African American patients were more likely than white patients to develop TD after long-term exposure to dopamine-blocking agents.

Oxidative stress and environmental influence can play into an individual’s risk for TD, Mufti told MedPage Today. Concomitant mood disorders, substance use disorder, intellectual disability, and central nervous system injuries also may raise TD risk, according to practice guidelines from the American Psychiatric Association.

While some risk factors aren’t modifiable, Zahed suggested avoiding alcohol and recreational drugs, engaging in regular exercise, or using non-pharmacologic interventions like therapy and psychosocial support to help manage psychiatric symptoms, when possible.

“There is some limited evidence that vitamin E may protect against worsening in TD but there is no convincing evidence that it prevents it entirely, and the studies so far have been small,” she added.

Certain genes are potentially implicated in TD, and they tend to be ones also implicated in schizophrenia, said Lauriello. Some research has identified gene polymorphisms involving antipsychotic metabolism and dopamine functioning.

TD genetic testing isn’t part of standard clinical practice, Zahed pointed out. “This is largely because known genetic risk factors so far can’t predict TD with enough accuracy to guide treatment choices,” she said. “Often, when antipsychotics are used, there are no drastically safer options for which genetic testing could change management. That said, this is an active area of research which, hopefully, will evolve in the near future.”

Treatment Variables

Zahed said her prescribing habits “absolutely” change when thinking about TD. “I typically tend to avoid first-generation antipsychotics in most patients in the outpatient setting,” she said. “Regardless of the antipsychotic, I start at the lowest possible dose and titrate slowly, particularly in patients with multiple risk factors for TD. Careful and slow discontinuation can be just as important.”

Otherwise known as “typical” or conventional antipsychotics, first-generation antipsychotics hit the market in the 1950s. Second-generation antipsychotics — or atypical antipsychotics — were first approved in the 1990s.

“First generations have about a 10-times greater risk of TD than the second generations,” Lauriello said. “The annual incidence of TD with a drug like [first-generation] haloperidol is about 5% a year. That means in the first 10 years, you’ve got a 50% chance of getting tardive dyskinesia because it’s 5% every year for the first 10 years.”

“Second-generation antipsychotics have around a 0.7% to 1% rate a year,” he added. “In the first 10 years, you’re talking about a 7% rate, or even a 10% rate at worst.”

With first-generation drugs, “the dose that gets you better is the dose that makes you stiff,” he said. “Atypicals are called atypical because the dose that gets you better is much lower than the dose that gets you stiff. If you’re not stiff, then you’re not necessarily as high a risk of getting TD.”

Second-generation antipsychotics carry risk for metabolic adverse events like weight gain, Lauriello noted. “But if I had to trade, I would trade the metabolics for the EPS [extrapyramidal symptoms],” he said.

“In some cases, we saw that if you switch to some atypicals, the tardive dyskinesia could get better, or even go away,” he added. “But you shouldn’t count on that.”

Even with atypical antipsychotics, clinicians should keep in mind that TD risk is never zero, Lauriello said. “It’s a bit of a warning that if you really don’t need to use an antipsychotic, you may want to not use an antipsychotic,” he advised. “If you need it, you need it, but it isn’t without a theoretical cost — even the atypicals. You always have to be cautious.”

Other dopamine-blocking medications can increase TD risk. Anti-nausea medications like metoclopramide (which carries a boxed warning on its label) and prochlorperazine can, too, said Zahed.

Some anticholinergic medications to manage chronic obstructive pulmonary disease, bladder control issues, or decrease Parkinson’s disease symptoms also have been linked with TD, said Mufti.

Cases have been reported with the use of antidepressants like amoxapine that work on dopamine receptors. Some obsessive-compulsive disorder, anxiety, depression, and attention-deficit/hyperactivity disorder agents could lead to TD, but at a lower rate than typical antipsychotics, Mufti added.

In rarer cases, lithium, antiseizure medications, antihistamines like hydroxyzine (also sometimes used for anxiety), antimalarials, decongestants, and anxiolytics also have been associated with TD.

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