VMAT2 inhibitors

Introduction

VMAT2 inhibitors are a class of pharmacologic agents that selectively inhibit the vesicular monoamine transporter type 2 (VMAT2), a protein responsible for packaging monoamine neurotransmitters—primarily dopamine, serotonin, norepinephrine, and histamine—into synaptic vesicles in presynaptic neurons. By inhibiting VMAT2, these drugs reduce the storage and subsequent synaptic release of monoamines, particularly dopamine. This mechanism is crucial in managing hyperkinetic movement disorders, including tardive dyskinesia (TD) and Huntington’s disease-related chorea.

The clinical significance of VMAT2 inhibitors has increased in recent years due to the recognition of tardive dyskinesia as a common side effect of long-term dopamine receptor-blocking agents (DRBAs), such as antipsychotics. The U.S. Food and Drug Administration (FDA) has approved several VMAT2 inhibitors specifically for these conditions.

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Pharmacological Mechanism

The VMAT2 transporter is located on the membranes of synaptic vesicles in monoaminergic neurons. It transports dopamine and other monoamines from the cytoplasm into vesicles for storage and subsequent release into the synaptic cleft. VMAT2 inhibitors act by binding to the transporter and preventing this uptake, which leads to reduced vesicular storage and increased cytosolic monoamine levels, especially dopamine. The excess cytosolic dopamine is then degraded by monoamine oxidase (MAO), ultimately leading to decreased dopamine availability in the synaptic cleft. This dampens dopaminergic neurotransmission, which is thought to contribute to the amelioration of hyperkinetic movements.

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Therapeutic Uses

1. Tardive Dyskinesia (TD): A persistent, involuntary movement disorder caused by chronic exposure to antipsychotic medications, especially typical antipsychotics and some atypicals. VMAT2 inhibitors are the only FDA-approved pharmacological treatment for TD.

2. Chorea associated with Huntington’s disease: Huntington’s chorea is characterized by excessive, involuntary movements due to dopaminergic overactivity in the striatum. VMAT2 inhibitors help mitigate these symptoms by decreasing synaptic dopamine levels.

3. Tourette Syndrome (Investigational use): Although not widely approved, VMAT2 inhibitors have shown some promise in reducing tics in Tourette syndrome.

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Approved Generic Drugs in the VMAT2 Inhibitor Class

1. Tetrabenazine

   • Indication: Chorea associated with Huntington’s disease

   • Mechanism: Reversibly inhibits VMAT2

   • Pharmacokinetics: Short half-life; extensively metabolized by CYP2D6

   • Common Side Effects: Depression, sedation, parkinsonism

   • FDA Approval: 2008

2. Deutetrabenazine

   • Indication: Tardive dyskinesia and chorea in Huntington’s disease

   • Mechanism: Deuterated form of tetrabenazine (longer half-life, more stable plasma concentration)

   • Pharmacokinetics: Improved pharmacokinetic profile vs tetrabenazine; metabolized by CYP2D6

   • Common Side Effects: Somnolence, diarrhea, dry mouth

   • FDA Approval: 2017

3. Valbenazine

   • Indication: Tardive dyskinesia (first FDA-approved drug for TD)

   • Mechanism: Selective VMAT2 inhibition

   • Pharmacokinetics: Once-daily dosing; metabolized by CYP3A4 and CYP2D6

   • Common Side Effects: Somnolence, QT prolongation, fatigue

   • FDA Approval: 2017

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Comparative Pharmacological Profiles

Property	Tetrabenazine	Deutetrabenazine	Valbenazine
FDA Approval Year	2008	2017	2017
Half-Life	4–8 hours	9–10 hours	15–22 hours
Dosing Frequency	3 times daily	Twice daily	Once daily
Major Metabolism	CYP2D6	CYP2D6	CYP3A4 and CYP2D6
QT Prolongation Risk	High	Moderate	Moderate
Sedation Risk	Moderate to high	Moderate	Low to moderate
Depression Risk	High	Lower than tetrabenazine	Minimal

Mechanistic Selectivity

These drugs primarily inhibit VMAT2, with little to no inhibition of VMAT1. VMAT1 is expressed predominantly in peripheral tissues and endocrine organs, while VMAT2 is more abundant in the central nervous system (CNS). Selectivity for VMAT2 is critical to reduce systemic side effects and focus therapeutic action within the brain.

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Dosage and Administration

• Tetrabenazine: Initial dose is typically 12.5 mg once or twice daily; titrated up to a maximum of 100 mg/day in divided doses.

• Deutetrabenazine: Usually initiated at 6 mg twice daily and increased weekly in 6 mg increments, up to 48 mg/day.

• Valbenazine: Initiated at 40 mg once daily, increased to 80 mg once daily after one week if tolerated.

Dose adjustments may be required based on CYP2D6 metabolizer status and hepatic function.

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Contraindications

• History of suicidal ideation or untreated depression (especially for tetrabenazine)

• Hepatic impairment (for deutetrabenazine and valbenazine)

• Use with MAO inhibitors (due to increased risk of serotonin syndrome and hypertensive crisis)

• QT prolongation or use with QT-prolonging drugs (valbenazine and tetrabenazine)

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Warnings and Precautions

• Depression and Suicidality: Particularly noted with tetrabenazine, less so with deutetrabenazine and valbenazine.

• Sedation and Somnolence: May impair physical and mental abilities.

• QT Prolongation: Valbenazine and tetrabenazine may increase QT interval; monitor ECGs in patients with existing heart conditions.

• Parkinsonism: Dopamine depletion may lead to symptoms resembling Parkinson’s disease.

• Neuroleptic Malignant Syndrome (NMS): Rare but potentially fatal; may occur when discontinuing dopamine-enhancing drugs.

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Drug Interactions

• MAO Inhibitors: Risk of hypertensive crisis or serotonin syndrome.

• Antidepressants (SSRIs, SNRIs, TCAs): May increase side effects such as serotonin syndrome and sedation; tetrabenazine may worsen depression when used with these agents.

• CYP2D6 Inhibitors (e.g., fluoxetine, paroxetine, quinidine): Increase plasma levels of tetrabenazine and deutetrabenazine, potentially requiring dose reductions.

• CYP3A4 Inhibitors/Inducers (for valbenazine): Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) may raise valbenazine levels; dose adjustments required.

• Alcohol and CNS Depressants: May enhance sedative effects.

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Special Populations

• Geriatric Use: Increased sensitivity to adverse effects, particularly sedation and parkinsonism.

• Hepatic Impairment: Use with caution; valbenazine is not recommended in severe hepatic impairment.

• Renal Impairment: Limited data, caution advised.

• Pregnancy and Lactation: Use only if clearly needed. Animal studies showed fetal toxicity with high doses. Human data are insufficient.

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Clinical Trials and Efficacy

• KINECT Trials (Valbenazine): KINECT 2 and KINECT 3 demonstrated statistically significant improvements in AIMS (Abnormal Involuntary Movement Scale) scores in patients with tardive dyskinesia.

• FIRST-HD Trial (Deutetrabenazine): Demonstrated significant reduction in chorea scores in Huntington’s disease patients.

• TETRA-HD Trial (Tetrabenazine): Supported efficacy in reducing Huntington’s chorea but highlighted concerns with depression and suicide risk.

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Future Directions and Research

There is ongoing research into the broader application of VMAT2 inhibitors for neuropsychiatric conditions including:

• Tourette syndrome

• Bipolar disorder

• Schizophrenia-related dyskinesias

• Treatment-resistant depression (as an adjunct therapy)

Novel VMAT2 inhibitors with improved selectivity and side effect profiles are also under investigation.