Addressing Challenges in the Management of Tardive Dyskinesia

Tardive dyskinesia (TD) is a hyperkinetic movement disorder primarily consisting of involuntary, repetitive movements that typically emerge after prolonged treatment with antipsychotic medications. While historically considered irreversible and highly stigmatized, the advent of FDA-approved therapies marks a new era in the management of this often-debilitating condition.

“Tardive dyskinesia is a hyperkinetic movement disorder that typically manifests in patients after they’ve been treated with antipsychotics for a prolonged period of time,” Lisa Whittington, PharmD, BCPS, BCPP, associate professor of clinical pharmacy at the Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences at the University of Southern California, said. “The primary challenges patients with tardive dyskinesia and their caregivers face in their daily lives cannot be overstated. It is enormous, and the condition of tardive dyskinesia impacts the overall quality of life of patients.”

Understanding the Disorder and Its Impact

TD manifests most commonly in the orofacial area, involving symptoms such as jaw movements, tongue thrusting, lip and cheek puckering, and excessive eye blinking. Though less frequent, movements can also occur in the trunk, limbs, and extremities.

The medications most known to induce TD are antipsychotics, categorized as first-generation (typical) and second-generation (atypical). While first-generation antipsychotics are the most common cause, TD also occurs with second-generation agents. The prevalence is estimated at approximately 25% among persons treated with antipsychotics, which are used for a range of indications beyond schizophrenia. Any medication that blocks dopamine, such as metoclopramide, also carries the potential to induce TD.

Certain patient populations face a higher risk, including adults aged 55 years or older; women, particularly middle-aged or older women who are Black or white; and individuals with a family history of TD. Other risk factors include earlier occurrences of extrapyramidal symptoms like dystonic reactions or Parkinson disease and the presence of mood disorders. Associated comorbidities, such as diabetes, hypertension, obesity, and tobacco or substance use, should also be considered by providers, although they do not necessarily cause TD.

The presence of TD significantly impacts a patient’s overall quality of life. Due to the prominence of involuntary movements in the orofacial region, patients often face difficulties in speech and communication. Daily activities are compromised; holding objects, exercising, writing, buttoning shirts, and even eating can become time-consuming or difficult, potentially leading to choking hazards.

“But another feeling, I think, [that is] common, is feeling embarrassed to go out into public and have people looking at you because you have these involuntary movements that are very visible that you can’t control,” Whittington said.

The psychological and social fallout is profound. Patients frequently experience sadness, frustration, anxiety, and worry about their symptoms worsening or how they are perceived by others. The visibility of the disorder leads to significant stigma, often resulting in patients limiting social activities, avoiding public transportation, or feeling embarrassed to appear in public. This stigma is compounded by the fact that the underlying severe mental illnesses, like schizophrenia and bipolar disorder, also remain highly stigmatized.

Diagnostic Challenges and Pharmacist Intervention

Diagnosis of TD is often missed or delayed. Symptoms can be disfiguring, causing patients to avoid seeking evaluation. This highlights the critical role of pharmacists, particularly those in community settings, who are highly accessible and may be the first to observe these symptoms.

“This is one of the key reasons why it’s really important for pharmacists to get involved, especially pharmacists who are in the community setting; they can see patients who may have these symptoms,” Whittington said.

Pharmacists must be adept at using the Abnormal Involuntary Movement Scale (AIMS) assessment to identify and rate the severity of involuntary movements in the facial, oral, extremity, and trunk regions. Specialty pharmacists should proactively screen all patients receiving antipsychotics using the AIMS. Establishing a strong rapport with patients, especially those with mental health disorders, allows pharmacists to serve as a trusted touchpoint for symptom identification and referral to specialists.

Evolution of Treatment Strategies

Historically, management options for TD were limited, relying primarily on interventions with only low to moderate evidence. Before FDA-approved options, providers often considered lowering the antipsychotic dose or switching to a different agent, most commonly clozapine. However, these strategies carry significant risks, including the potential for withdrawal dyskinesia, which may become chronic, symptom worsening, or relapse of the patient’s underlying psychiatric condition. Providers must carefully weigh the risk vs benefit, especially when considering discontinuing a highly effective antipsychotic regimen.

Today, the 2 FDA-approved medications for TD are VMAT2 inhibitors: deutetrabenazine and valbenazine.

“Their primary mechanism of action is they inhibit VMAT2 receptors,” Whittington said. “What they do is they regulate the monoamine uptake to the synaptic vesicle, and in doing so, they decrease dopamine storage and release, and that in turn decreases the stimulation of the [D₂ dopamine] receptors in the motor striatum.”

Deutetrabenazine comes in immediate release (IR) and extended release (XR) tablet formulations. The XR tablet, administered once daily, may improve adherence compared with the twice-daily IR formulation. Titration takes approximately 7 weeks to reach the maximum dose of 48 mg. Deutetrabenazine is contraindicated in hepatic impairment.

Valbenazine is a capsule dosed once daily. It allows for a faster titration, potentially reaching the maximum dose of 80 mg within about a week. Notably, a sprinkle capsule formulation, which can be opened and mixed with soft food, is available for patients with swallowing difficulties. Valbenazine does not require dosage adjustments for mild or severe renal impairment.

Both medications have demonstrated statistically significant improvements on the AIMS scale in phase 3 clinical trials, confirming their efficacy for moderate to severe TD.

Safety and Adherence

Pharmacists are crucial in patient education regarding adverse effects (AEs) and adherence. Common AEs for both VMAT2 inhibitors include fatigue, diarrhea, and akathisia. Valbenazine specifically carries a warning for depression and suicidal ideation. Proactive patient education, including a discussion of risk vs benefit, is essential, as patients who are not educated about potential AEs are at a higher risk of premature discontinuation.

Drug-drug interactions require careful monitoring. Both deutetrabenazine and valbenazine require dose adjustments if the patient is taking a strong CYP2D6 inhibitor or is a poor metabolizer of the enzyme. Valbenazine also requires adjustments with strong CYP3A4 inhibitors and should be avoided with strong inducers of the same enzyme. Pharmacogenetic testing may be considered to identify poor metabolizers prior to initiation.

Finally, financial burdens pose a significant barrier to medication adherence and access, as these therapies can be expensive. Pharmacists must assist patients in accessing treatment via financial options, such as patient assistance programs, low-income subsidies, or co-pay cards, to ensure continuity of care. Pharmacists must also commit to destigmatizing TD and mental health conditions to foster the open communication necessary for optimal management.

“One of the most common challenges that the pharmacist faces in ensuring medication adherence and access to treatment for persons with tardive dyskinesia is definitely financial burdens associated with the therapies because these are relatively new medications,” Whittington said.