Vortioxetine

Vortioxetine (brand names Trintellix, Brintellix) is a prescription antidepressant approved for the treatment of major depressive disorder (MDD) in adults.

It is indicated for patients experiencing depressive episodes and has been studied for cognitive symptoms associated with depression.

Vortioxetine acts as a serotonin modulator and stimulator: it inhibits the serotonin transporter and exerts agonist or antagonist effects at various 5-HT receptors (agonist at 5-HT_1A, partial agonist at 5-HT_1B, and antagonist at 5-HT₃, 5-HT_1D, and 5-HT₇), which enhances serotonergic signaling and helps improve mood.

Vortioxetine is primarily metabolized by the liver enzyme CYP2D6, part of the cytochrome P450 family responsible for processing many medications. CYP2D6 converts vortioxetine into inactive metabolites that are subsequently eliminated from the body.

Variations in the CYP2D6 gene can alter enzyme activity: some people metabolize vortioxetine very quickly, while others process it slowly or at an intermediate rate. These differences can affect drug levels and response.

Individuals classified as poor metabolizers of CYP2D6 may experience increased vortioxetine plasma concentrations and a higher risk of side effects, whereas ultrarapid metabolizers may have lower concentrations, potentially reducing therapeutic benefits. Intermediate and normal metabolizers generally fall between these extremes, with intermediate metabolizers potentially experiencing mild increases in drug levels.

Ultrarapid Metabolizer

• Effect on drug levels: Significantly lower plasma concentrations.
• Clinical consequence: Decreased probability of clinical benefit.
• Side effects: Fewer side effects (mild and infrequent), but may experience subtherapeutic response.

Normal Metabolizer

• Effect on drug levels: Expected therapeutic concentrations.
• Clinical consequence: Standard efficacy and tolerability.
• Side effects: Typical side effects (mild-to-moderate, common), such as nausea or headache.

Intermediate Metabolizer

• Effect on drug levels: Slightly increased plasma concentrations.
• Clinical consequence: Small increase in probability of side effects.
• Side effects: Mild side effects (e.g., nausea, dizziness) and occasional moderate discomfort.

Poor Metabolizer

• Effect on drug levels: Much higher plasma concentrations.
• Clinical consequence: Increased risk of adverse effects.
• Side effects: Moderate-to-severe side effects (e.g., nausea, sexual dysfunction), more frequent.

Indeterminate/Not available

• Effect on drug levels: Unknown impact.
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring.
• Side effects: Unknown; monitor patient response.

CYP2D6 Dosing Guideline

Examples of alternative antidepressants that are not predominantly metabolized by CYP2D6 include citalopram, escitalopram, and sertraline. These options may be considered for patients with ultrarapid or poor CYP2D6 metabolizer status.

• CPIC – Guideline for Selective Serotonin Reuptake Inhibitors and CYP2D6 and CYP2C19
• FDA – Table of Pharmacogenetic Associations