vortioxetine

General Information

Vortioxetine (Trintellix) is a multimodal antidepressant approved for adult major depressive disorder; guidelines highlight it as a later-line option when first-line SSRIs/SNRIs are ineffective or poorly tolerated, and when cognitive symptoms persist.[label_vortioxetine][apa_mdd_2023][canmat_mdd_2024]

Weight-neutral metabolism and a relatively low interaction burden make vortioxetine attractive for patients already receiving antipsychotics or mood stabilizers, although cost remains a barrier because only authorized generics are available.

The contrast view and the vortioxetine evidence feed can help compare vortioxetine with other pro-cognitive antidepressants when reassessing residual cognitive symptoms or augmentation plans.

Consider when executive dysfunction or residual cognitive complaints remain problematic; provide nausea mitigation strategies during initiation.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Combines serotonin transporter inhibition with serotonergic receptor modulation: 5-HT1A agonism, 5-HT1B partial agonism, and 5-HT3/5-HT7/5-HT1D antagonism to influence downstream neurotransmitters including dopamine, norepinephrine, acetylcholine, and glutamate.[katona2018]

• SERT inhibitor; 5-HT1A agonist; 5-HT1B partial agonist; 5-HT3/5-HT7/5-HT1D antagonist; negligible histaminic or muscarinic activity.

Metabolism and Pharmacokinetics

• Peak concentrations occur 7–11 hours post-dose; food does not meaningfully affect exposure.[label_vortioxetine]
• Extensively metabolized hepatically—CYP2D6 is the primary pathway with contributions from CYP3A4/5 and CYP2C9; inactive metabolites are excreted in urine and feces.[label_vortioxetine]
• Terminal half-life ≈66 hours (steady state in ~2 weeks); about 59% of a dose is recovered in urine and 26% in feces, mainly as metabolites (<1% unchanged).[label_vortioxetine]

Dosing and Administration

• Initiate 10 mg once daily; increase to 20 mg once daily after at least 7 days if tolerated.[label_vortioxetine]
• When co-administered with strong CYP2D6 inhibitors (bupropion, fluoxetine, paroxetine, quinidine) or in known poor metabolizers, consider 5 mg once daily with a maximum of 10 mg daily.[label_vortioxetine]
• Extended taper is usually unnecessary due to the long half-life, but stepping down to 10 mg for one week before stopping can minimize transient discontinuation symptoms.

Monitoring & Labs

• Suicidality and psychiatric activation during initiation and dose changes, especially in younger adults.[label_vortioxetine]
• Nausea and early GI tolerability during the first 1–2 weeks; supportive care and dosing time adjustments can prevent premature discontinuation.
• Sodium in older adults or patients on diuretics if symptoms suggest hyponatremia (confusion, fatigue, falls).[label_vortioxetine]
• Medication reconciliation for CYP2D6 inhibitors/inducers that can shift exposure and tolerability.[label_vortioxetine]
• Mood elevation or mixed features in bipolar-spectrum illness; coordinate monitoring plans via the bipolar disorder hub.

Vortioxetine’s main tolerability limiter is nausea; most other monitoring is SSRI-class safety (suicidality early, hyponatremia risk, serotonergic interaction checks).

Adverse Effects

Interactions

• Strong CYP2D6 inhibitors increase vortioxetine exposure—do not exceed 10 mg/day and monitor for nausea or dizziness.[label_vortioxetine]
• Enzyme inducers (carbamazepine, rifampin) may reduce efficacy; consider higher doses (up to 20 mg) while monitoring response or choose an alternative.[label_vortioxetine]
• Contraindicated with MAOIs, linezolid, or IV methylene blue—allow a 14-day washout to reduce serotonin syndrome risk.[label_vortioxetine]
• Additive bleeding risk with NSAIDs, antiplatelets, or anticoagulants—consider gastroprotection and counsel on bleeding signs.

Other Useful Information

• Randomized studies (FOCUS, CONNECT) suggest improvements in cognitive domains such as processing speed and executive function; track functional gains over time.[thase2016_vortioxetine]
• Because nausea is the primary tolerability barrier, provide supportive care (ginger, antiemetics PRN) and consider slower titration in sensitive patients.

References

1. Trintellix (vortioxetine) prescribing information — DailyMed (2024)
2. Vortioxetine: a review of its use in major depressive disorder — CNS Drugs (2014)
3. Efficacy of vortioxetine on cognitive functioning in depression: FOCUS study — International Journal of Neuropsychopharmacology (2016)
4. Comparative efficacy and acceptability of 21 antidepressant drugs for major depressive disorder — The Lancet (2018)Meta-analysisdepressionefficacy
5. APA Clinical Practice Guideline for the Treatment of Depression — American Psychiatric Association (2023)Guidelinedepressionclinical
6. CANMAT 2024 Clinical Guidelines for Major Depressive Disorder — Canadian Journal of Psychiatry (2024)