Vortioxetine

Usage

• Medical Conditions: Vortioxetine is prescribed for Major Depressive Disorder (MDD) in adults.
• Pharmacological Classification: An antidepressant. More specifically, it’s a serotonin modulator and stimulator (SMS).
• Mechanism of Action: Vortioxetine has a multimodal action on serotonergic targets, including serotonin transporter inhibition, 5-HT_1A receptor agonism, 5-HT_1B receptor partial agonism, 5-HT₃, 5-HT₇, and 5-HT_1D receptor antagonism. This complex interaction is thought to enhance serotonergic neurotransmission in various brain regions relevant to mood regulation.

Alternate Names

• No widely used alternate generic names exist.
• Brand Names: Brintellix, Trintellix.

How It Works

• Pharmacodynamics: Vortioxetine enhances serotonergic activity through its multimodal mechanism, which affects several serotonin receptors and the serotonin transporter. This leads to increased serotonin levels in the synaptic cleft, improving mood and other symptoms associated with depression. It also affects noradrenergic, dopaminergic, histaminergic, cholinergic, and GABAergic systems.

• Pharmacokinetics:

  • Absorption: Well-absorbed orally, with an absolute bioavailability of about 75%. Food does not significantly affect absorption.
  • Metabolism: Extensively metabolized in the liver, primarily by CYP2D6. Other CYP enzymes involved include CYP3A4/5, CYP2C9, CYP2C19, and CYP2B6. The major metabolite is inactive.
  • Elimination: Elimination half-life is approximately 66 hours, reaching steady-state plasma concentration in about 2 weeks. Excreted primarily in the urine (2/3) as inactive metabolites, with about 1/3 eliminated in the feces. Only negligible amounts of unchanged vortioxetine are excreted in the feces.

• Mode of Action: Vortioxetine binds to and modulates the activity of multiple serotonin receptors and inhibits the serotonin transporter (SERT). This leads to complex effects on serotonin neurotransmission, distinct from selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs).

• Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation:

  • SERT inhibition.
  • 5-HT_1A receptor agonism.
  • 5-HT_1B receptor partial agonism.
  • 5-HT₃, 5-HT₇, and 5-HT_1D receptor antagonism.

• Elimination Pathways: Primarily hepatic metabolism via multiple CYP enzymes, followed by renal excretion of inactive metabolites.

Dosage

Standard Dosage

Adults:

• Initial dose: 10 mg orally once daily.
• Maintenance dose: Increase to 20 mg/day as tolerated. If 20 mg/day is not tolerated, consider decreasing the dose to 5 mg/day.
• Dosing frequency: Once daily.
• Maximum dose: 20 mg/day (10 mg/day for CYP2D6 poor metabolizers).

Children:

• Not indicated for use in patients under 18 years of age. Safety and efficacy have not been established.

Special Cases:

• Elderly Patients (≥65 years): Initial dose: 5 mg orally once daily. Increase to 10 mg/day with caution, as tolerated. Limited data exists for doses exceeding 10 mg/day in this population.
• Patients with Renal Impairment: No dose adjustment is necessary. However, caution is advised in patients with severe renal impairment.
• Patients with Hepatic Dysfunction: No dose adjustment is generally recommended for mild or moderate hepatic impairment. Caution is advised in moderate or severe hepatic impairment. Vortioxetine has not been studied in patients with severe hepatic impairment and is not recommended in these patients.
• Patients with Comorbid Conditions: Careful monitoring and dose adjustment may be needed in patients with certain comorbid conditions. For example, patients with a history of seizures or unstable epilepsy should be monitored closely.

Clinical Use Cases

Vortioxetine is not indicated for use in settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its sole indication is for the treatment of MDD.

Dosage Adjustments

• CYP2D6 Poor Metabolizers: Maximum recommended dose is 10 mg/day.
• CYP2D6 Inhibitors (e.g., bupropion, fluoxetine, paroxetine, quinidine): Reduce vortioxetine dose by half. Increase back to the original dose when the inhibitor is discontinued.
• CYP Inducers (e.g., rifampin, carbamazepine, phenytoin): Consider increasing the vortioxetine dose (maximum 3 times the original dose). Reduce back to the original dose when the inducer is discontinued.

Side Effects

Common Side Effects:

Nausea, constipation, vomiting, dizziness, dry mouth, sexual dysfunction, abnormal dreams.

Rare but Serious Side Effects:

Serotonin syndrome, hyponatremia, bleeding abnormalities (especially when combined with NSAIDs, aspirin, or other anticoagulants), mania/hypomania, suicidal thoughts or behavior (especially in young adults), angle-closure glaucoma, seizures.

Long-Term Effects:

Potential for sexual dysfunction and other chronic side effects with prolonged use.

Adverse Drug Reactions (ADR):

Serotonin syndrome, severe hyponatremia, allergic reactions, suicidal ideation/behavior, significant bleeding, manic episodes, seizures.

Contraindications

• Hypersensitivity to vortioxetine.
• Concurrent use of Monoamine Oxidase Inhibitors (MAOIs) or use within 14 days of discontinuing an MAOI. Allow at least 21 days after stopping vortioxetine before starting an MAOI.
• Concurrent use with linezolid or intravenous methylene blue.

Drug Interactions

• MAOIs: Contraindicated (risk of serotonin syndrome).
• Serotonergic drugs (e.g., SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort): Increased risk of serotonin syndrome.
• CYP2D6 Inhibitors: Increased vortioxetine levels.
• CYP Inducers: Decreased vortioxetine levels.
• NSAIDs/Aspirin/Anticoagulants: Increased risk of bleeding.
• Alcohol: May enhance sedative effects.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C (US FDA). Data are limited. Animal studies have shown developmental toxicity. Use only if the potential benefit outweighs the potential risk to the fetus.
• Breastfeeding: Vortioxetine and/or its metabolites are present in human milk. The effects on a nursing infant are unknown. Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the mother’s clinical need for vortioxetine.

Drug Profile Summary

• Mechanism of Action: Multimodal serotonergic agent (SERT inhibitor, 5-HT_1A receptor agonist, 5-HT_1B receptor partial agonist, 5-HT₃, 5-HT₇, and 5-HT_1D receptor antagonist).
• Side Effects: Nausea, constipation, vomiting, dizziness, dry mouth, sexual dysfunction; rarely, serotonin syndrome, hyponatremia, bleeding, mania/hypomania, suicidal thoughts/behavior.
• Contraindications: Hypersensitivity, concurrent MAOI use, linezolid, intravenous methylene blue.
• Drug Interactions: MAOIs, serotonergic drugs, CYP2D6 inhibitors/inducers, NSAIDs/aspirin/anticoagulants.
• Pregnancy & Breastfeeding: Caution advised; potential fetal risk; drug excreted in breast milk.
• Dosage: Adults: 10–20 mg once daily; Elderly: initially 5 mg/day, may increase to 10 mg/day; CYP2D6 PMs: 10 mg/day maximum.
• Monitoring Parameters: Monitor for mood changes, suicidal thoughts/behavior, symptoms of serotonin syndrome, hyponatremia, and signs of bleeding.

Popular Combinations

While vortioxetine is often used as monotherapy, it may be combined with other medications (e.g., other antidepressants, anxiolytics, mood stabilizers) in certain cases under careful monitoring by a healthcare professional. Information about “popular combinations” can vary widely based on individual patient needs and clinical practice. Consulting up-to-date clinical guidelines and expert advice is crucial for appropriate combination therapy.

Precautions

• General Precautions: Evaluate patients for bipolar disorder, mania, or hypomania before initiating treatment. Monitor for suicidal thoughts or behavior, especially early in treatment and during dosage changes. Assess for bleeding risk, particularly in patients taking anticoagulants or NSAIDs. Monitor electrolytes, especially sodium levels.
• Specific Populations: As detailed in the “Dosage” section above.
• Lifestyle Considerations: Alcohol may enhance sedative effects. Caution patients about operating machinery until they know how vortioxetine affects them.

FAQs (Frequently Asked Questions)

Q1: What is the recommended starting dose of vortioxetine?

A: 10 mg orally once daily for adults under 65 years of age. 5 mg orally once daily for adults 65 years and older.

Q2: Can vortioxetine be used in children?

A: No, vortioxetine is not indicated for use in patients under 18 years of age.

Q3: What is the maximum dose of vortioxetine?

A: 20 mg/day for most adults. 10 mg/day for CYP2D6 poor metabolizers.

Q4: How should vortioxetine be discontinued?

A: While vortioxetine can be discontinued abruptly, it is recommended that doses of 15 mg/day or 20 mg/day be reduced to 10 mg/day for 1 week prior to discontinuation to minimize potential withdrawal symptoms (e.g., headache, muscle tension).

Q5: What are the most common side effects of vortioxetine?

A: Nausea, constipation, vomiting, dizziness, dry mouth, and sexual dysfunction.

Q6: What are the serious side effects of vortioxetine to watch out for?

A: Serotonin syndrome, hyponatremia, bleeding abnormalities, mania/hypomania, and suicidal thoughts or behavior.

Q7: Can vortioxetine be taken with other antidepressants?

A: Combining vortioxetine with other serotonergic antidepressants can increase the risk of serotonin syndrome and requires careful monitoring and dose adjustment. Other combinations may be possible but should be considered on a case-by-case basis by a physician.

Q8: Does vortioxetine interact with any other medications?

A: Yes, vortioxetine interacts with MAOIs (contraindicated), other serotonergic drugs, CYP2D6 inhibitors/inducers, and NSAIDs/aspirin/anticoagulants.

Q9: Can vortioxetine be used during pregnancy or breastfeeding?

A: Vortioxetine’s safety during pregnancy and breastfeeding has not been fully established. Use with caution and only if the potential benefit outweighs the risk. The drug is present in breast milk, and the effects on nursing infants are unknown.

Q10: What should patients be advised about taking vortioxetine?

A: Patients should be informed about the potential side effects, drug interactions, and the importance of reporting any mood changes or suicidal thoughts. Advise patients to avoid alcohol or use with caution and to be careful about driving or operating machinery until they know how the medication affects them. Patients should also be advised not to abruptly discontinue treatment without consulting their doctor, especially if they are on higher doses. They should also be encouraged to discuss any pre-existing medical conditions and other medications they are taking with their physician.