Adequately Addressing Tardive Dyskinesia: Clinical Tips and Insights

The use of antipsychotic medications is increasing in Western countries, primarily related to increased nonpsychotic indications and some off-label use.^1-3 There are concerns that clinicians underestimate the risk of potential adverse effects associated with second-generation antipsychotics (SGAs).^4,5 Despite a general perception that SGAs are safer than those in the first generation, data suggest that along with the nearly doubling of use of SGAs, there has been a doubling in the rates of antipsychotic overdoses, with the same level of consequent morbidity and mortality.¹

One of the most troubling adverse effects of antipsychotic medications is tardive dyskinesia (TD). TD is a severe and frequently permanent movement disorder that occurs as a consequence of chronic use of dopamine-blocking agents, which include some antipsychotics and some antiemetics. Concerns over the induction of TD were the main driver of clinicians’ switch from first-generation antipsychotic (FGA) to SGA medications.⁶ Indeed, the annualized risk of developing TD with SGAs was less than half than the risk associated with FGAs (6.5%, 95% CI, 5.3%‐7.8% vs 2.6%, 95% CI, 2.0%‐3.1%; RR=0.47, 95% CI, 0.39‐0.57, P < .0001). However, TD risk is associated with upregulation of the dopaminergic pathways, and that is related to the extent of blockade of the D2 receptors,⁷ so it is not surprising that the risk of developing TD increases in a dose-dependent manner independent of whether the drug was an FGA or SGA.⁸ This is related to the fact that an increased dose is generally associated with increased D2 receptor occupancy, and if receptor occupancy of a D2 antagonist exceeds 80%, there is a significant increase in parkinsonism and eventual TD.⁹

Recognizing Risk Factors

Parkinsonism and the use of anticholinergic agents are among the best predictors of the eventual development of TD,⁷ and anticholinergic agents, such as benztropine, actually make TD worse.¹⁰ Consequently, reducing the antipsychotic dose is the preferred management strategy for drug-induced parkinsonism.¹⁰ Additional risk factors include longer duration of antipsychotic treatment, mood disorder diagnosis, being female, and advancing age.^11,12

Once TD develops, African American ancestry is associated with a poorer prognosis.¹³ Early detection is essential to optimize outcome.¹⁴ Dose reduction or use of an anti-TD drug can improve the course of this complication.¹⁴ Screening is generally recommended annually or every 6 months, and with in-person use of the Abnormal Involuntary Movement Scale¹⁵ or the Extrapyramidal Symptom Rating Scale, which is more cumbersome because it rates both parkinsonism and TD.¹⁶ Although any striated muscle can be impacted, the most highly innervated muscles are more susceptible, which means that the orofacial muscles and the index fingers and thumb are frequently the first to display abnormal movements. Since parkinsonism is frequent, it is important to distinguish dyskinetic movements from parkinsonian tremor. Early in the course of TD, the first abnormal movements may be fasciculations of muscles on the surface of the tongue. To distinguish TD from other movement disorders that occur in patients, such as parkinsonism and mannerisms, one should remember that TD is random and unpredictable, whereas mannerisms and tremor are repetitious and predictable.

Minimize Exposure

Once TD is recognized, clinicians should minimize exposure to the offending agent. This generally means discontinuation or reduction of the dose of the antipsychotic drug, if possible. Switching to antipsychotics with a low affinity to dopamine, such as clozapine or quetiapine, is frequently recommended.^17,18 The muscarinic agonist antipsychotic xanomeline/trospium has not been used in patients with TD, and an older review of procholinergic drugs in the treatment of TD (which included xanomeline without trospium) could not find a reliable effect—either way—on TD.¹⁹ One should consider starting a vesicular monoamine transport (VMAT) inhibitor. In the central nervous system, this is VMAT2.²⁰ This is a reasonable therapeutic target since TD is related to upregulation of the dopamine system. While this is frequently thought of as “dopamine receptor supersensitivity,” it is actually related to increases in dopamine release, the number of dopaminergic synapses, and the increase in expression of postsynaptic receptors.⁷ Inhibition of VMAT2 results in reduced quantities of dopamine release and turnover, which reduces the abnormal movements.

Psychopharmacologic Interventions

Tetrabenazine is a specific VMAT2 inhibitor that is effective for TD but has unreliable pharmacokinetics.^21,22 Innovative modifications have resulted in 2 unique agents that are effective for TD: valbenazine (Ingrezza) and deutetrabenazine (Austedo).^23-25 Valbenazine links the tetrabenazine molecule to an amino acid, valine. The valine must be cleaved with a peptidase from the valbenazine molecule to release the active tetrabenazine. This slows down the release of free tetrabenazine in a predictable manner. Deutetrabenazine replaces some of the hydrogen molecules on tetrabenazine with deuterium, which slows down its metabolism. Both these agents are available as single daily doses and have similar adverse effect profiles. Both have demonstrated reductions in TD symptoms without any evidence of inducing progression of the TD or any rebound worsening after discontinuation.²⁶ The reductions of the abnormal movements are approximately 50% from baseline but associated with marked improvement in function.²⁷

Concluding Thoughts

TD can be quite disabling with consequences that exceed the physical movements with induction of self-consciousness and reduction of self-confidence and quality of life. Unfortunately, when modern FGAs were introduced, clinicians believed that parkinsonism was necessary to achieve the therapeutic antipsychotic effect. Consequently, commonly used doses of FGAs are more likely to induce movement disorders. If FGAs are used, one needs to always determine the minimal effective dose. The brain’s adaptive changes resulting from chronic antipsychotic treatment may result in a progressive need to increase the dose or potency of the antipsychotic medication. In this light, clinicians should consider initiating treatment in naive patients with partial agonist agents since they cause fewer changes.²⁸Augmentation can be accomplished with antioxidants including ginkgo biloba extracts, vitamin B6, vitamin E, Coenzyme Q10 (CoQ10), and N-acetylcysteine (NAC), which act as antioxidants and may reduce neuronal degeneration.²⁹ Complications (eg, intolerance to VMAT2 inhibitors) can be addressed with use of clonazepam.²⁹ Should TD progress and become more severe than that managed by VMAT2 inhibitors or if the involvement of a specific muscle is causing dangerous medical problems (eg, pharyngeal TD), one can consider botulinum toxin (onabotulinumtoxinA) or deep brain stimulation.²⁹

Dr El-Mallakh is a professor in the Department of Psychiatry and Behavioral Sciences and director of the Mood Disorders Research Program at the University of Louisville School of Medicine in Kentucky.

Ms Woods is a nurse practitioner practicing medicine in Louisville, Kentucky.

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