Volume 15 | ORIGINALLY PUBLISHED March 2024/UPDATED JULY 2024

Classifying Tardive Dyskinesia (TD) and Drug-Induced Parkinsonism (DIP) as EPS Leads to Misdiagnosis and Inappropriate Use of Anticholinergics in TD

Long-term management
A Deep Dive Into the Neurobiology of Tardive Dyskinesia and Drug-Induced Parkinsonism
A Deep Dive Into the Neurobiology of Tardive Dyskinesia and Drug-Induced Parkinsonism

Tardive dyskinesia (TD) and drug-induced parkinsonism (DIP) are common movement disorders experienced by patients taking dopamine receptor blocking agents, the active agent in many antipsychotic drugs.1-3 While the symptoms of TD and DIP may have some similarities, these disorders are caused by opposing mechanisms, and treatment for one can exacerbate the symptoms of the other.1,2 It is, therefore, imperative to be able to effectively distinguish between the two. Understanding the causes of TD and DIP can help contextualize their treatment.1,4

While the symptoms of TD and DIP may have some similarities, these disorders are caused by opposing mechanisms, and treatment for one can exacerbate the symptoms of the other.1,2

Normally, movement is controlled by dopamine signaling in the basal ganglia.5 The presynaptic neuron receives a signal to initiate movement and a postsynaptic neuron transmits the signal to produce movement.4,5

Dopamine is present in the presynaptic neuron and is packaged into synaptic vesicles via vesicular monoamine transporter 2.4,5 When the signal to initiate movement is received by the presynaptic neuron, the vesicles fuse with the presynaptic membrane and release dopamine into the synapse.4,5 Dopamine then binds to dopamine D2 receptors on the postsynaptic neuron.4,5 Then a signal is transmitted to the postsynaptic neuron, ultimately resulting in movement.4,5

In DIP, the initiation or increase in the dose of an antipsychotic leads to the acute blockade of the dopamine receptors, which results in decreased dopamine signaling.4 Thus, when dopamine is released, the antipsychotic is bound to dopamine receptors, and the blockade results in reduced dopamine signaling in the postsynaptic neuron. Reduced dopamine signaling results in bradykinesia or slowness of movement.4

The exact pathophysiology of TD is not fully understood. However, it is thought that in TD, chronic blockade of dopamine receptors by the antipsychotic results in the upregulation of dopamine receptor function, possibly due to hypersensitivity or an increase in the number of dopamine receptors. This results in increased dopamine signaling, which manifests as the excessive movements characteristic of TD.1,4

In summation, although TD and DIP are both movement disorders associated with patients taking antipsychotic drugs, they occur due to opposing mechanisms within the dopaminergic pathway.1,2 In DIP, the blockade of dopamine reduces dopamine signaling, subsequently resulting in hypokinetic movement such as bradykinesia (Figure 1).4 In TD, there is upregulation of dopamine receptors, resulting in increased dopamine signaling, which manifests as hyperkinetic movement.1,4

Figure 1: TD and DIP Have Different Causes
AB

Given these differing etiologies, the differing symptoms of each disorder, and the implications of misdiagnosis, it is important to base treatment decisions on accurate diagnosis of TD and DIP.1,4

References
1. Hauser RA, Meyer JM, Factor SA, et al. Differentiating tardive dyskinesia: a video-based review of antipsychotic-induced movement disorders in clinical practice. CNS Spectr. 2022;27(2):208-217. 2. Miller JJ. Everyone please stop (EPS). Psychiatr Times. 2022;39(8). 3. Ogino S, Miyamoto S, Miyake N, Yamaguchi N. Benefits and limits of anticholinergic use in schizophrenia: focusing on its effect on cognitive function. Psychiatry Clin Neurosci. 2014;68(1):37-49. 4. Ward KM, Citrome L. Antipsychotic-related movement disorders: drug-induced parkinsonism vs. tardive dyskinesia-key differences in pathophysiology and clinical management. Neurol Ther. 2018;7(2):233-248. 5. Sonne J, Goyal A, Lopez-Ojeda W. Dopamine. In: StatPearls [Internet]. StatPearls Publishing; 2023. Accessed December 4, 2023. https://www.ncbi.nlm.nih.gov/books/NBK535451/
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Overview of TD and DIP
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Treatment
AUSTEDO XR: A Once-Daily First-Line Treatment for Tardive Dyskinesia
Past Volumes
Volume 14
Understanding the Long-Term Nature of TD and Its Impact on the Underlying Mental Health Condition
Read more
Volume 13
Exploring the Nurse Practitioner's Role in the Screening and Assessment of Patients for Tardive Dyskinesia
Read more
Volume 11
The Critical Need to Accurately Differentiate Tardive Dyskinesia Versus Drug-Induced Parkinsonism
Read more
Volume 10
Screening and Assessment of TD With a Focus on the Virtual Visit
Read more
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IMPORTANT SAFETY INFORMATION
Depression and Suicidality in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. Balance the risks of depression and suicidality with the clinical need for treatment of chorea. Closely monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior. Inform patients, their caregivers, and families of the risk of
IMPORTANT SAFETY INFORMATION
Depression and Suicidality in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO can increase the risk of depression
INDICATIONS AND USAGE

AUSTEDO XR® (deutetrabenazine) extended-release tablets and AUSTEDO® (deutetrabenazine) tablets are indicated in adults for the treatment of chorea associated with Huntington's disease and for the treatment of tardive dyskinesia.

IMPORTANT SAFETY INFORMATION
Depression and Suicidality in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. Balance the risks of depression and suicidality with the clinical need for treatment of chorea. Closely monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior. Inform patients, their caregivers, and families of the risk of depression and suicidality and instruct them to report behaviors of concern promptly to the treating physician. Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation. AUSTEDO XR and AUSTEDO are contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression.
Contraindications AUSTEDO XR and AUSTEDO are contraindicated in patients with Huntington's disease who are suicidal, or have untreated or inadequately treated depression. AUSTEDO XR and AUSTEDO are also contraindicated in: patients with hepatic impairment; patients taking reserpine or within 20 days of discontinuing reserpine; patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing MAOI therapy; and patients taking tetrabenazine or valbenazine.
Clinical Worsening and Adverse Events in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO may cause a worsening in mood, cognition, rigidity, and functional capacity. Prescribers should periodically re-evaluate the need for AUSTEDO XR or AUSTEDO in their patients by assessing the effect on chorea and possible adverse effects.
QTc Prolongation: AUSTEDO XR and AUSTEDO may prolong the QT interval, but the degree of QT prolongation is not clinically significant when AUSTEDO XR or AUSTEDO is administered within the recommended dosage range. AUSTEDO XR and AUSTEDO should be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.
Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex reported in association with drugs that reduce dopaminergic transmission, has been observed in patients receiving tetrabenazine. The risk may be increased by concomitant use of dopamine antagonists or antipsychotics. The management of NMS should include immediate discontinuation of AUSTEDO XR and AUSTEDO; intensive symptomatic treatment and medical monitoring; and treatment of any concomitant serious medical problems.
Akathisia, Agitation, and Restlessness: AUSTEDO XR and AUSTEDO may increase the risk of akathisia, agitation, and restlessness. The risk of akathisia may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops akathisia, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy.
Parkinsonism: AUSTEDO XR and AUSTEDO may cause parkinsonism in patients with Huntington's disease or tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors. The risk of parkinsonism may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops parkinsonism, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy.
Sedation and Somnolence: Sedation is a common dose-limiting adverse reaction of AUSTEDO XR and AUSTEDO. Patients should not perform activities requiring mental alertness, such as operating a motor vehicle or hazardous machinery, until they are on a maintenance dose of AUSTEDO XR or AUSTEDO and know how the drug affects them. Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.
Hyperprolactinemia: Tetrabenazine elevates serum prolactin concentrations in humans. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of AUSTEDO XR and AUSTEDO.
Binding to Melanin-Containing Tissues: Deutetrabenazine or its metabolites bind to melanin-containing tissues and could accumulate in these tissues over time. Prescribers should be aware of the possibility of long-term ophthalmologic effects.
Common Adverse Reactions: The most common adverse reactions for AUSTEDO (>8% and greater than placebo) in a controlled clinical study in patients with Huntington's disease were somnolence, diarrhea, dry mouth, and fatigue. The most common adverse reactions for AUSTEDO (4% and greater than placebo) in controlled clinical studies in patients with tardive dyskinesia were nasopharyngitis and insomnia. Adverse reactions with AUSTEDO XR extended-release tablets are expected to be similar to AUSTEDO tablets.
Please see accompanying full Prescribing Information, including Boxed Warning.
INDICATIONS AND USAGE

AUSTEDO XR® (deutetrabenazine) extended-release tablets and AUSTEDO® (deutetrabenazine) tablets are indicated in adults for the treatment of chorea associated with Huntington's disease and for the treatment of tardive dyskinesia.

IMPORTANT SAFETY INFORMATION
Depression and Suicidality in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. Balance the risks of depression and suicidality with the clinical need for treatment of chorea. Closely monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior. Inform patients, their caregivers, and families of the risk of depression and suicidality and instruct them to report behaviors of concern promptly to the treating physician. Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation. AUSTEDO XR and AUSTEDO are contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression.
Contraindications AUSTEDO XR and AUSTEDO are contraindicated in patients with Huntington's disease who are suicidal, or have untreated or inadequately treated depression. AUSTEDO XR and AUSTEDO are also contraindicated in: patients with hepatic impairment; patients taking reserpine or within 20 days of discontinuing reserpine; patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing MAOI therapy; and patients taking tetrabenazine or valbenazine.
Clinical Worsening and Adverse Events in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO may cause a worsening in mood, cognition, rigidity, and functional capacity. Prescribers should periodically re-evaluate the need for AUSTEDO XR or AUSTEDO in their patients by assessing the effect on chorea and possible adverse effects.
QTc Prolongation: AUSTEDO XR and AUSTEDO may prolong the QT interval, but the degree of QT prolongation is not clinically significant when AUSTEDO XR or AUSTEDO is administered within the recommended dosage range. AUSTEDO XR and AUSTEDO should be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.
Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex reported in association with drugs that reduce dopaminergic transmission, has been observed in patients receiving tetrabenazine. The risk may be increased by concomitant use of dopamine antagonists or antipsychotics. The management of NMS should include immediate discontinuation of AUSTEDO XR and AUSTEDO; intensive symptomatic treatment and medical monitoring; and treatment of any concomitant serious medical problems.
Akathisia, Agitation, and Restlessness: AUSTEDO XR and AUSTEDO may increase the risk of akathisia, agitation, and restlessness. The risk of akathisia may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops akathisia, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy.
Parkinsonism: AUSTEDO XR and AUSTEDO may cause parkinsonism in patients with Huntington's disease or tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors. The risk of parkinsonism may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops parkinsonism, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy.
Sedation and Somnolence: Sedation is a common dose-limiting adverse reaction of AUSTEDO XR and AUSTEDO. Patients should not perform activities requiring mental alertness, such as operating a motor vehicle or hazardous machinery, until they are on a maintenance dose of AUSTEDO XR or AUSTEDO and know how the drug affects them. Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.
Hyperprolactinemia: Tetrabenazine elevates serum prolactin concentrations in humans. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of AUSTEDO XR and AUSTEDO.
Binding to Melanin-Containing Tissues: Deutetrabenazine or its metabolites bind to melanin-containing tissues and could accumulate in these tissues over time. Prescribers should be aware of the possibility of long-term ophthalmologic effects.
Common Adverse Reactions: The most common adverse reactions for AUSTEDO (>8% and greater than placebo) in a controlled clinical study in patients with Huntington's disease were somnolence, diarrhea, dry mouth, and fatigue. The most common adverse reactions for AUSTEDO (4% and greater than placebo) in controlled clinical studies in patients with tardive dyskinesia were nasopharyngitis and insomnia. Adverse reactions with AUSTEDO XR extended-release tablets are expected to be similar to AUSTEDO tablets.
Please see accompanying full Prescribing Information, including Boxed Warning.