Back Back
TD Psychopharmacology
Tardive Dyskinesia: Pharmacologic Interventions and Clinical Implications

Released: November 27, 2024

Expiration: November 26, 2025

Greg W. Mattingly
Greg W. Mattingly, MD
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • Although TD may initially be recognized because of the appearance of tremors, it comprises a range of motor symptoms that significantly affect the well-being of patients and lead to social stigma.
  • Regular screening of patients treated with dopamine-modulating medication with a tools such as the Abnormal Involuntary Movement Scale (AIMS) can help to achieve early detection of TD and differentiation from other movement disorders.
  • The VMAT2 inhibitors deutetrabenazine and valbenazine are both approved by the FDA for safe and effective treatment of TD; dosing considerations may affect the choice of medication for each patient.

In April 2017, in a historic breakthrough, the first of 2 VMAT2 inhibitors (valbenazine and, later that year, deutetrabenazine) was approved by the FDA for the treatment of tardive dyskinesia (TD), bringing hope to individuals living with this often chronic and irreversible movement disorder. Although treatment initially focused on the motoric effects of TD, often forgotten were the increased emotional distress, stigma, and social isolation that develop as a result of having TD. 

Tremors, Parkinson’s Disease, or TD
Tardive, from the root word tardis or tardy, refers to a late-occurring movement disorder that is a dyskinesia (ie, abnormal movement often seen as distressing or disfiguring). By definition, TD is a late-occurring movement disorder that is significantly different than that resulting from a medication. Medication-induced tremors can frequently result from numerous agents prescribed for physical or mental health conditions; they typically begin when a medication is initiated or increased in dose and improve as the dose is decreased or the medication is discontinued.  

Tremors, by definition, have a consistent rhythmicity and frequency similar to what can be experienced during stress or caffeine exposure. Tremors are frequently seen with a variety of common medications including those used to treat asthma or depression, psychostimulants, and mood stabilizers such as lithium or valproate. Drug-induced parkinsonism involves a resting tremor with consistent frequency and symptoms associated with muscle rigidity and bradykinesia. Associated symptoms such as festinating gait, micrographia, retropulsion, “pill-rolling” tremors, and “masked” or decreased facial expression are frequently experienced.  

Evaluating the Risks
Risk factors for TD include exposure to antipsychotic or dopamine-modulating medications. Of importance, when screening for TD, remember that atypical antipsychotics are no longer focused on psychotic illnesses: 90% are used for other mental health conditions including mood disorders, posttraumatic stress disorder, autism, Alzheimer’s disease, insomnia, and various forms of agitation. 

Total cumulative exposure (ie, the number of years and total cumulative prescribed dose), gender, and age are other well-known risk factors. Most studies have shown that women have an elevated risk for TD and that risk increases dramatically during the perimenopausal and postmenopausal years. Estrogen changes the way dopamine binds to dopamine receptors, and fluctuations in estrogen levels associated with perimenopause and menopause increase TD risk. Various associated mental and physical health conditions (eg, developmental disabilities, autism spectrum disorders, diabetes, prior stroke, and head trauma) also appear to increase TD risk and make the brain more vulnerable to its development. A recent study of TD in a Veterans Affairs population found that underlying diabetes significantly increased the risk of associated TD. Antipsychotic medication choice and dopamine potency also increase the risk of TD, with older/traditional dopamine D2 receptor–selective antipsychotics having a higher relative risk than the newer generation of dopamine partial agonists. In addition, the use of benztropine may further accelerate the disease course and is not recommended by the American Psychiatric Association. 

Beyond Tremors 
When the impact of TD is investigated, it is imperative that patients be asked not only about purely motoric effects but also about the associated impacts on their mental and physical well-being. Recent studies have shown that TD has a significant impact on social withdrawal and stigma. A recent survey found that among individuals with TD, 72% felt embarrassed to leave their home, 74% reported difficulty swallowing, 82% reported that it was difficult to enjoy activities they previously enjoyed, and 86% reported difficulty falling asleep. 

Three takeaways from this survey are that TD 1) has a significant impact on both physical and emotional well-being, 2) has a significant effect on swallowing and increases the risk of aspiration in vulnerable individuals, and 3) can be frequently confused with restless legs syndrome (RLS) and lead to the inappropriate prescribing of RLS medicines, which will only complicate and potentially worsen TD. 

Recognition and Screening
Although TD can affect any part of the body, certain places are neurologically more vulnerable. TD is highly prevalent in muscles involving the lips, tongue, eyes, fingers, and hands. In 40% of individuals, muscles below the waist including the hips, legs, and feet are affected.  

A variety of tools can be used to screen for TD, with the Abnormal Involuntary Movement Scale (AIMS) being the gold standard in most mental health clinics. The AIMS is used to assess 7 body regions, and each is scored on a scale of 0-4 (0, none; 1, minimal; 2, mild; 3, moderate; 4, severe). These items focus on the eyes, muscles associated with facial expression, lips, tongue, fingers, hands, legs, feet, neck, shoulders, and hips. This scale is also used to measure disease severity and follow improvements during treatment. 

FDA-Approved Treatments: Which to Choose?
In 2017, valbenazine and deutetrabenazine were approved for treatment. Although both are VMAT2 inhibitors, they have unique pharmacologic properties that may make one more preferable for certain patients. 

Deutetrabenazine is a deuterated derivative of tetrabenazine. Tetrabenazine, the first VMAT2 inhibitor approved for the treatment of involuntary movements caused by Huntington’s disease, has limitations because of its short half-life, and it requires repeated dosing with a multitude of active metabolites that bind to VMAT2 and numerous off-target receptors. Deutetrabenazine was modified by placing a deuterated or “heavy” hydrogen molecule on one of the tetrabenazine side chains. This modification slows the metabolism of and allows twice-daily dosing of the original formulation, and allows once-daily dosing of the extended-release formulation. Deutetrabenazine, metabolized more slowly, similarly converts into 4 isomers with varying selectivity for VMAT2 and off-target receptors for dopamine, serotonin, and norepinephrine. Because of these off-target receptors, deutetrabenazine use must be initiated at a subtherapeutic dose (6 or 12 mg) and titrated to a therapeutic range (24-48 mg/day). The degree of VMAT2 inhibition is increased with dose titration, with the highest overall improvement is seen at 36-48 mg. Deutetrabenazine is recommended to be given with food and there is a significant food effect.

Valbenazine was approved for TD in April 2017. Both valbenazine and its single metabolite are highly selective for VMAT2, with very little off-target receptor binding. The longer half-life of valbenazine allows for once-daily dosing with an initial dosage of 40 mg/day, which is significantly effective for improving symptoms. Valbenazine may be given once daily (morning or evening), with or without food, and titrated from an initial therapeutic dose of 40 mg to 60 or 80 mg during the course of 1 week. Valbenazine is also available in a sprinkle formulation, which may be preferential for those with swallowing difficulties. In clinical trials, sedation was the only adverse effect (significantly higher than with placebo) and appeared to be dose related. Both valbenazine and deutetrabenazine offer hope to improve functional outcomes, decrease stigma, and improve quality of life in individuals living with TD. 

Your Thoughts?
In your practice, what do you find most challenging to manage in patients with TD? Get involved in the discussion by answering the polling question and posting a comment below.

Continue

Poll

1.

In your practice, what aspect of TD do you find most challenging to manage?

Submit