What is Vortioxetine (Trintellix)?

Vortioxetine (Trintellix): A Multimodal Antidepressant

Vortioxetine is a novel multimodal antidepressant medication that works through both serotonin transporter inhibition and modulation of multiple serotonin receptors, used primarily for treating major depressive disorder (MDD) with unique benefits for cognitive function. 1

Mechanism of Action

• Vortioxetine inhibits the serotonin transporter (5-HTT) with high affinity (Ki=1.6 nM) while also acting on multiple serotonin receptors 1
• Functions as an antagonist at 5-HT3, 5-HT1D, and 5-HT7 receptors, a partial agonist at 5-HT1B receptors, and an agonist at 5-HT1A receptors 1, 2
• This multimodal mechanism distinguishes it from traditional SSRIs and SNRIs, potentially contributing to its unique clinical profile 2, 3
• At therapeutic doses, vortioxetine achieves approximately 50% serotonin transporter occupancy at 5 mg/day, 65% at 10 mg/day, and 80% at 20 mg/day 1

Clinical Applications

• FDA-approved for the treatment of major depressive disorder in adults 1
• Demonstrated efficacy in both short-term (8 weeks) and long-term (52 weeks) treatment of depression 4
• Shows particular benefit in improving cognitive function in depression, with significant improvements in executive function, attention, processing speed, learning, and memory 5, 3
• May be effective as a second-line treatment after SSRI or SNRI failure, with studies showing superiority to agomelatine in this context 4

Pharmacokinetics

• Administered orally once daily with a recommended starting dose of 10 mg 1, 6
• Linear and dose-proportional pharmacokinetics with a mean terminal half-life of approximately 66 hours 6
• Steady-state plasma concentrations generally achieved within 2 weeks of dosing 6
• Mean absolute oral bioavailability of 75% with no significant food effect 6
• Metabolized primarily through CYP2D6 enzyme pathways, with dose adjustments recommended for CYP2D6 poor metabolizers 1, 6

Adverse Effects

• Most common adverse effects include nausea (occurring in 21-32% of patients), which is dose-related and typically decreases in frequency over time 1
• Other common side effects include dizziness, constipation, vomiting, and sexual dysfunction 1, 3
• May have a more favorable sexual side effect profile compared to some other antidepressants 3
• Like other antidepressants, carries a black box warning for increased risk of suicidal thoughts and behaviors, particularly in young adults 1
• Risk of serotonin syndrome when combined with other serotonergic medications 1

Dosing Considerations

• Available in tablet form in strengths of 5 mg, 10 mg, and 20 mg 1
• Recommended starting dose is 10 mg once daily, which can be increased to 20 mg daily as needed 1, 6
• Dose should be reduced to 5 mg daily in CYP2D6 poor metabolizers 1
• Dose adjustments should be considered when used with strong CYP2D6 inhibitors (like bupropion) or CYP inducers (like rifampin) 6

Clinical Pearls

• Vortioxetine's unique procognitive effects make it particularly valuable for patients with depression who experience cognitive dysfunction 5, 3
• The drug's multimodal mechanism may provide benefits beyond those of traditional SSRIs or SNRIs 2, 3
• When selecting antidepressants, consider vortioxetine for patients where cognitive symptoms are prominent or when sexual dysfunction is a concern with other medications 7
• The American College of Physicians recommends selecting second-generation antidepressants based on adverse effect profiles, cost, and patient preferences 8
• Regular assessment of therapeutic response and adverse effects should begin within 1-2 weeks of initiation 8