Vortioxetine (Trintellix/Brintillex)

Primer

Vortioxetine (Trade name: Trintellix/Brintillex) is an antidepressant in the serotonin modulator and stimulator class used in the treatment of major depressive disorder.

Pharmacokinetics

Pharmacokinetics of Vortioxetine

Absorption
Distribution
Metabolism
Elimination
Half-life 57 hours

Vortioxetine: Cytochrome P450 Metabolism

Substrate of (Metabolized by)
Induces
Inhibits

Pharmacodynamics

Mechanism of Action

  • Similar vilazodone, vortioxetine acts like an SSRI but also has direct serotonin receptor interactions that is thought to theoretically add to its clinical benefit. It has the following actions:
  • Serotonin (5-HT) transporter (SERT) inhibition
    • This is also the primary mechanism of action of classic antidepressants like SSRIs and SNRIs.
  • Serotonin (5-HT) receptor agonism:
    • 5-HT1A agonism
      • Which theoretically can enhance downregulation of presynaptic 5-HT1A receptors and lead to more robust disinhibition of serotonin release
  • Serotonin (5-HT) receptor partial agonism:
    • 5-HT1B partial agonism
      • Thought to have potential antidepressant effects.[1]
  • Serotonin (5-HT) receptor antagonism:
    • 5-HT3 antagonism
      • Despite vortioxetine having 5-HT3 antagonism (which is anti-nausea), there is a high incidence of nausea and vomiting.[2][3]
    • 5-HT1D antagonism
      • Thought to have impact on anxiety and vascular vasoconstriction in the brain.
    • 5-HT7 antagonism
      • Is thought give pro-cognitive effects (not clinically proven, nor approved by FDA!)

Toxicity

  • Vortioxetine is relatively non-toxic in overdose

Indications

  • Major depressive disorder
  • Anxiety disorders

Dosing

Dosing for Vortioxetine

Starting 10 mg
Titration Increase by another 10 mg after 1 to 2 weeks, depending on tolerability
Maximum 20 mg
Taper Long-half life, self-tapering, no withdrawal side effects

Formulations

  • Vortioxetine comes in an oral formulation

Monitoring

Contraindications

Absolute

Relative

Drug-Drug Interactions

Side Effects

  • Nausea (more so than other SSRIs), vomiting, constipation; possibly less sexual SE, sedation and weight gain

Cognition

  • Currently marketed by pharmaceutical companies as having more improvement on cognitive effects of depression (but this claim is very questionable).
    • This marketing strategy was based on studies showing slightly better performance on the digit substitution test, which is only a single domain test, and not a comprehensive cognitive assessment.[4]
    • The FDA in fact rejected the drug manufacturer’s request to claim that vortioxetine improved cognition in depression based on this poor quality study data.[5]
    • However, the drug company Lundbeck decided to market it saying it is “the first FDA-approved treatment for MDD to have data in the U.S. Prescribing Information showing a positive effect on processing speed.”[6]
    • Importantly, this is not the same as having FDA approval to market the drug for the actual treatment of cognitive dysfunction in depression!

Adverse Events

Clinical Pearls

Special Populations

Geriatric

Pediatric

Obstetric and Fetal

Medically Ill

Resources

References

1) Tiger, M., Varnäs, K., Okubo, Y., & Lundberg, J. (2018). The 5-HT 1B receptor-a potential target for antidepressant treatment. Psychopharmacology, 235(5), 1317-1334.
2) Wagner, G., Schultes, M. T., Titscher, V., Teufer, B., Klerings, I., & Gartlehner, G. (2018). Efficacy and safety of levomilnacipran, vilazodone and vortioxetine compared with other second-generation antidepressants for major depressive disorder in adults: A systematic review and network meta-analysis. Journal of affective disorders, 228, 1-12.
3) Aydin, O., & Ünal-Aydin, P. (2017). Vortioxetine-induced nausea and its management. Psychiatry and Clinical Psychopharmacology, 27(3), 325.
4) The Carlat Psychiatry Report, Volume 18, Number 10, October 2020
5) Mullard, A. FDA rejects first cognitive claim for antidepressant. Nat Rev Drug Discov 15, 299 (2016).
6) FDA updates Trintellix® (vortioxetine) label to include data showing improvement in processing speed, an important aspect of cognitive function in acute Major Depressive Disorder (MDD)