Old Challenges and New Directions in Managing Tardive Dyskinesia

Tardive dyskinesia is a condition characterized by involuntary movements of the oral, lingual, and buccal regions that is typically observed in patients who have been treated with antipsychotic agents on a long-term basis.¹

Tardive dyskinesia was originally described in 1957 after the first antipsychotic agents were introduced.² Although tardive dyskinesia is primarily associated with first-generation antipsychotics (FGAs), it is now understood that it can also be associated with second-generation antipsychotics (SGAs), although the risk is lower.

“Once the [FGAs] fell out of favor largely because of [extrapyramidal symptoms], second-generation agents became more frequently used and were regarded as more benign, in terms of [tardive dyskinesia],” observed Christoph Correll, MD, professor at the Center for Psychiatric Neuroscience at the Feinstein Institute for Medical Research and medical director of the Recognition and Prevention Program in the Department of Psychiatry at the Zucker Hillside Hospital, Manhassett, New York.

Clinicians treating patients using SGAs began to focus on their metabolic adverse effects, which became “much more of an issue,” and so the focus on tardive dyskinesia was “no longer on the forefront of their minds,” he told Psychiatry Advisor.

Epidemiology

Contrary to expectation, tardive dyskinesia has not disappeared with the lower-risk SGAs³. A recent estimate of the incidence of newly diagnosed cases of tardive dyskinesia in 2016 was 26,000 patients (90% CI, 21,000-30,000 patients), translating to an incidence rate of 10.6 per 100,000 US adults.⁴ Prevalence (number of patients with diagnosed tardive dyskinesia) in 2016 was estimated to be 9% of the general antipsychotic user population, with 32% of the prevalence pool experiencing “severe” tardive dyskinesia.⁴ Another study suggested rates of tardive dyskinesia are as high as 20.7% with SGAs and 30.0% with FGAs.⁵

Because the indications and off-label uses for antipsychotic medications have expanded to include nonpsychotic bipolar disorder, unipolar depression, anxiety disorders, and insomnia, more patients are receiving antipsychotics than in the past.¹ The incidence of tardive dyskinesia is therefore likely to increase, mainly driven by anticipated ongoing increases in the number of patients treated with antipsychotics.¹

Pathophysiology of Tardive Dyskinesia

The pathophysiology of tardive dyskinesia “lacks a universally accepted theory and mechanism.”⁶ Prolonged blockade of postsynaptic dopamine receptors may lead to dopamine receptor supersensitivity, gamma-aminobutyric acid depletion, cholinergic deficiency, oxidative stress, altered synaptic plasticity, neurotoxicity, and defective neuroadaptive signaling.⁶ Some evidence also points to a genetic predisposition to tardive dyskinesia.⁶

Risk Factors for Tardive Dyskinesia

One of the major risk factors for the development is tardive dyskinesia is older age.¹ Compared with the annual incidence of tardive dyskinesia in the general adult population taking antipsychotics, the incidence in older adults (mean age, 78.3) is considerably higher (0.8% vs 5.3%).⁷

Other risk factors include female sex, African American ethnicity, preexisting mood disorder, impaired cognition, alcohol/substance abuse, higher dose of antipsychotic medications, longer duration of antipsychotic medication use, treatment with first-generation antipsychotics medications, use of lithium or antiparkinsonian agents, early occurrence of extrapyramidal symptoms, diabetes, and HIV positivity.¹

Preventing tardive dyskinesia

Tardive dyskinesia is sometimes irreversible, so clinicians should make sure to take preventive measures that limit its risk, Dr Correll said. This includes following the prescribing information for each agent, limiting long-term use to cases in which discontinuing the medication would lead to worsening illness (eg, psychotic conditions); dosing medication carefully until efficacy has been achieved, and then not increasing the dose more than necessary; and engaging in regular monitoring and assessment.

Assessing Tardive Dyskinesia

Tardive dyskinesia is underassessed, according to Dr Correll.

“Since the current generation of psychiatrists has been raised on SGAs and has relatively little experience with FGAs, keeping tardive dyskinesia in mind is not, on the whole, part of their experience or training,” he said.

The onset of tardive dyskinesia can be “insidious” because it presents with “fluctuating symptoms that can be masked by or confused with symptoms of other disorders or medication-induced side effects.”¹

Involuntary orofacial movements may include chewing, lip smacking, puckering or pursing, tongue protrusion, grimacing, or bulging cheeks. In addition, tardive dyskinesia can involve the extremities and include contracting, twisting, or writhing movements of fingers, hands, arms, and legs.¹

“The first thing to do is realize that tardive dyskinesia does take place, differentiate it from other conditions like [extrapyramidal symptoms] or tremor, and recognize that it is not simply a mannerism or an intrinsic part of the illness,” Dr Correll said.

Other conditions, including nonmedicated schizophrenia, can also include movement disturbances and should be considered in the differential diagnosis of tardive dyskinesia. These include: spontaneous dyskinesias, Huntington disease, senile chorea, chronic motor tic disorder, autism, Wilson disease, Meige syndrome, Syndenham chorea, Tourette syndrome, Rett syndrome, restless leg syndrome, oral problems (eg, ill-fitting dentures), or medication adverse effects from drugs other than antipsychotics, such as stimulants, caffeine, antihistamines, phenytoin, estrogens, or antidepressants.¹

There are 2 sets of criteria frequently used for diagnosing tardive dyskinesia: the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),⁸ and the Schooler-Kane criteria.⁹ They are summarized here.