Mechanism of Disease

DIP and TD are caused by typical and atypical antipsychotic drugs (APDs) that block D2 receptors.

DIP and TD are both caused by typical or atypical APDs blocking D2 receptors, which then changes the nature of dopamine signaling across the synapse. This signaling is altered in different ways depending on whether the exposure to APDs is acute, as in DIP, or chronic, as in TD. These distinctions result in the different clinical manifestations seen in DIP and TD.

 
  • Dopamine receptors on dopamine neurons play a key role in mediating normal movement
  • DIP results from a short-term blockade of D2 receptors, which reduces dopamine signaling and decreases movement
  • TD is caused, in part, by an upregulation of dopamine receptors in response to a chronic D2 blockade, ultimately leading to increased dopamine signaling and excessive movement
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PerfecTD:

Pencil and open spiral notebook with √TD written in it.

Question 1 of  

DIP is: (use the drop-down menus to select the correct answer, then click REVEAL ANSWER.)

The

short-term

short-term

chronic

blockade of D2 receptors leads to

reduced

increased

reduced

dopamine signaling. This, in turn, leads to changes in the brain’s motor pathway that result in

reduced

reduced

excessive

movement.

Answers:

In DIP, short-term blockade of D2 receptors leads to reduced dopamine signaling. This is consistent with the acute onset of symptoms in DIP. Reduced dopamine signaling leads to the reduced movement, characteristic of DIP.

TD is: (use the drop-down menus to select the correct answer, then click REVEAL ANSWER.)

The

chronic

short-term

chronic

blockade of D2 receptors causes
a(n)

upregulation

upregulation

downregulation

of dopamine receptor activity, ultimately leading to

increased

increased

reduced

dopamine signaling. This, in turn, leads to changes in the brain’s motor pathway that result in

excessive

reduced

excessive

movement.

Answers:

The chronic blockade of D2 receptors causes an upregulation of dopamine receptor activity, ultimately leading to increased dopamine signaling. This, in turn, leads to changes in the brain’s motor pathway that result in excessive movement.

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DIP vs TD: Chapter 2

Pathophysiology

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Summary:

Although DIP and TD may both be caused by typical and atypical APDs blocking D2 receptors, the duration of APD exposure
impacts dopamine signaling in very different ways, resulting in fundamentally different clinical manifestations.

Explore the Next Chapter
Symptoms

Chapter 2 References:

Hauser RA et al. CNS Spectr. 2022;27(2):208-217.

Sonne J et al. In: StatPearls [Internet]. StatPearls Publishing; 2022. Accessed April 4, 2023. https://www.ncbi.nlm.nih.gov/books/NBK535451.

Ward KM, Citrome L. Neurol Ther. 2018;7(2):233-248.

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.