Vortioxetine Guide: Pharmacology, Indications, Dosing Guidelines and Adverse Effects

In a nutshell

Vortioxetine combines serotonin reuptake inhibition with direct modulation of multiple serotonin receptors, potentially offering advantages for patients with cognitive symptoms of depression. Its main clinical advantage appears to be a favorable tolerability profile, particularly regarding sexual dysfunction and discontinuation symptoms.

• Choosing vortioxetine over other antidepressants:
  • Preferred for patients with prominent cognitive symptoms of depression
  • Lower risk of sexual dysfunction compared to SSRIs
  • Minimal discontinuation symptoms due to long half-life
  • Low risk of drug interactions (except with CYP2D6 inhibitors/inducers)
• Consider alternatives when:
  • Patients sensitive to GI side effects (high rates of nausea)
  • Treating anxiety disorders (insufficient evidence for GAD)
  • Cost is a concern (newer branded medication)
  • Concurrent use of strong CYP2D6 inhibitors/inducers

Pharmacodynamics and mechanism of action

• Multimodal mechanism combining serotonin reuptake inhibition with direct modulation of serotonin receptors ^[1]
• Primary mechanism: Potent serotonin reuptake inhibition through SERT blockade ^[2]
• Direct receptor activity ^[2,3]
  • Agonist: 5-HT1A receptor
  • Partial agonist: 5-HT1B receptor
  • Antagonist: 5-HT1D, 5-HT3, 5-HT7 receptors
• Preclinical findings and potential implications
  • While vortioxetine’s receptor binding profile distinguishes it from traditional SSRIs, the clinical significance of these pharmacological differences continues to be investigated ^[2].
  • 5-HT1A agonism
    • May accelerate antidepressant response through somatodendritic receptor desensitization ^[2,4]
  • 5-HT3 antagonism
    • May enhance anxiolytic and antidepressant effects ^[2]
  • 5-HT7 antagonism
    • Potentially enhances antidepressant effects when combined with SERT inhibition ^[2]
    • May be linked to pro-cognitive effects ^[5]
  • Combined 5-HT1B partial agonism and SERT inhibition
    • Increased serotonin levels in the prefrontal cortex and enhanced serotonergic neuron firing have been described in animal models ^[6].

Pharmacokinetics

Metabolism

• Primarily metabolized through oxidation via CYP2D6 ^[3]
• Minor pathways involve other CYP450 isoenzymes (CYP3A4/5, CYP2C19, CYP2C9, etc).
• CYP2D6 metabolism
  • CYP2D6 metabolizer status affects plasma concentrations
  • Poor metabolizers exhibit approximately double the plasma concentrations compared to extensive metabolizers.
  • Maximum recommended dose for CYP2D6 poor metabolizers is 10 mg/day ^[3]
• Vortioxetine levels increased by
  • Strong CYP2D6 inhibitors (bupropion, fluoxetine, paroxetine, quinidine
    • Reduce vortioxetine dose by 50%
    • Return to original dose when inhibitor is discontinued
• Vortioxetine levels reduced by
  • Strong CYP inducers (rifampin, carbamazepine, phenytoin)
    • Consider increasing vortioxetine dose
    • Maximum dose should not exceed 3 times the original dose
    • Return to original dose within 14 days of discontinuing the inducer ^[7]
• Serotonergic agents 
  • Monitor for serotonin syndrome with other serotonergic medications (SSRIs, SNRIs, triptans, tricyclic antidepressants). 
  • Also applies to tramadol, tryptophan, and St. John’s Wort
• Contraindicated with MAOIs ^[3]
  • Due to vortioxetine’s long half-life, a 21-day washout period is required after discontinuation before starting an MAOI.
  • A 14-day washout period is required after discontinuing an MAOI before initiating vortioxetine.

Half-life

• Vortioxetine half-life is approximately 66 hours.

False-positive drug tests

• Vortioxetine can trigger false-positive methadone results in urine immunoassays ^[3]
  • Confirmatory testing via chromatographic methods is recommended for positive screens.

Dosage forms

Dosage forms

• Immediate-release:
  • Film-coated tablets
    • 5 mg, 10 mg, 20 mg
    • Trintellix
• Formulation considerations
  • Tablets can be taken with or without food, at either morning or bedtime.

Indications

FDA-Approved Indications

Major depressive disorder

• First-line antidepressant treatment option for MDD based on efficacy and favorable tolerability profile ^[8,9]
• Shows advantages over other antidepressants when considering both efficacy and acceptability in network meta-analyses ^[10]
• Cognitive effects:
  • The labeling includes data showing improvements in cognitive processing speed (as measured by the Digit Symbol Substitution Test)
  • Despite seeking separate regulatory approval, vortioxetine was not approved for cognitive symptoms of depression as a standalone indication.
  • May be particularly beneficial for patients with cognitive symptoms (problems with concentration, memory, and executive functioning), and age-related cognitive decline ^[11,12]
  • Recent systematic review reports superior efficacy compared to SSRIs ^[13]
    • Half to two-thirds of the observed effect of vortioxetine on cognitive improvement is a direct effect on cognition itself, rather than being a consequence of improvements in depressive symptoms.
• Dosing:
  • Starting dose: 10 mg once daily
    • Sensitive patients: Start at 5 mg once daily for patients who experience nausea or who do not tolerate higher doses
  • Target dose: 20 mg/day
  • Maximum dose:
    • General population: 20 mg/day
    • CYP2D6 poor metabolizers: 10 mg/day ^[3]
  • May be taken day or night, independent of food intake

Off-label Uses

Generalized anxiety disorder

• The evidence does not support vortioxetine for use in GAD ^[14,15]

Obsessive compulsive disorder

• There are no double-blind studies investigating vortioxetine’s efficacy in OCD ^[16]
• However, case report indicates vortioxetine’s potential role for depressed patients with obsessive symptoms ^[17], or in OCD patients unsuitable for TCAs or unresponsive to SSRIs ^[18,19].

Side effects

Most common side effects

Gastrointestinal

• Nausea (21-32% incidence)
  • Most common adverse effect leading to discontinuation
  • Usually occurs in the first week, with 15-20% experiencing nausea after 1-2 days of treatment ^[3].
  • Dose-related: Approximately 10% still experience nausea at treatment end with doses 10-20mg/day
  • Can be minimized by taking it with food
• Diarrhea (7-10% incidence)
• Dry mouth (7% incidence)
• Constipation (3-6% incidence)
• Vomiting (3-6% incidence)

Other common side effects

• Discontinuation syndrome
  • Lower risk compared to other antidepressants due to vortioxetine’s 66-hour half-life ^[20,21]
  • Clinical trials and observational data suggest low incidence and/or similar to placebo ^[21,22]
  • For 15-20mg/day doses, a reduction to 10mg/day for one week before discontinuation is recommended ^[3]
• Antidepressant-induced sexual dysfunction
  • Lower rates of sexual dysfunction compared to other antidepressants ^[21,23]
    • However, spontaneous reporting likely underestimates actual prevalence ^[24]
  • Even though the effect is dose-dependent, treatment-emergent sexual dysfunction rates remain comparable to placebo ^[25]
  • May improve sexual function in patients switching from high-risk antidepressants (e.g., citalopram, paroxetine, or sertraline) ^[23]
  • Consider lower doses for patients concerned about sexual side effects
  • Use structured assessment tools like the ASEX rather than relying on spontaneous reporting
  • Monitor for dose-dependent effects
• Dizziness (6-9% incidence)
• Abnormal dreams (2-3% incidence)
• Pruritus (2-3% incidence)

Severe side effects

• Serotonin syndrome
  • Risk increases with other serotonergic drugs
  • Has also been reported in monotherapy ^[26]
  • Use caution when combining vortioxetine with serotonergic medications, especially during treatment initiation or dose adjustments ^[3].
• Bleeding risk
  • Serotonergic antidepressants (SSRIs, SNRIs) may increase bleeding risk, particularly with concurrent NSAIDs, antiplatelets or anticoagulants.
  • Vortioxetine may share this risk, though current evidence is limited
  • In healthy volunteers, coadministration with warfarin or aspirin did not alter coagulation parameters ^[27].
  • Clinical data in depressed populations remain sparse; monitor closely when combined with anticoagulants, especially at initiation ^[28].
• Hyponatremia
  • Antidepressant therapy can precipitate SIADH and clinically significant hyponatremia.
  • Ranking of risk ^[29]:
    • MAOIs > SNRIs > SSRIs > TCAs > Mirtazapine
    • Vortioxetine was not included in this meta-analysis, but cases have been documented ^[30–32].
  • Special caution in elderly patients, patients taking diuretics or who are otherwise volume-depleted

Use in special populations

Pregnancy

• First-trimester safety
  • Animal reproductive studies of vortioxetine show no evidence of increased congenital malformation risk during pregnancy.
  • Limited human data from a case series of 17 first-trimester exposures reported ^[33]
• Pregnancy complications
  • Late pregnancy exposure may be associated with ^[3]
    • Neonatal adaptation syndrome
    • Persistent pulmonary hypertension of the newborn (PPHN)
    • Similar to other serotonergic antidepressants

Breastfeeding

• Vortioxetine is present in breast milk.
• FDA prescribing information notes lack of data on effects on breastfed infants and milk production ^[3]
• Available case reports suggest minimal infant exposure, but few cases and limited follow-up data ^[34]
  • Relative infant dose: 1.1-1.7% of maternal dose
  • Based on data from only 3 women taking 10-20 mg/day
• One additional case report describes successful breastfeeding for one year while on medication ^[33]
  • No follow-up information provided on infant outcomes
• Breastfed infants should be monitored for
  • Sedation
  • Poor feeding patterns
  • Weight gain adequacy
  • Development

Hepatic impairment

• No dose adjustment needed

Renal impairment

• No dose adjustment needed

Elderly

• No dose adjustment recommended ^[3]
• Starting dose 5 mg/day recommended ^[35]
• Caution with doses >10 mg/day due to
  • Increased risk of hyponatremia
  • Higher exposure (up to 27%) compared to younger adults

Obesity

• Mean elimination half-life prolonged by 48% in patients with BMI ≥35 kg/m² compared to normal BMI
• Consider extended washout period when switching to MAOIs in patients with obesity ^[36]

Brand names

• US: Trintellix
• Canada: Trintellix
• Other countries/regions: Acsodix, Brintellix, Brivor, Depratiox, Fonksera, Kelac, Lupivor, Procetina, Torvox, Trivoxetin, Trintogen, Valquir, Vantaxa, Vectax, Vipca, Vormind, Vorpix, Vorsero, Vortica, Vortidif, Vortiox, Vortiray, Vorxetil, Voxigain, Voxitin, Vorellix, Vivirum, Vorti, Vorasan, Vurtuoso, Xomet

References

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2. Sowa-Kućma, M., Pańczyszyn-Trzewik, P., Misztak, P., Jaeschke, R. R., Sendek, K., Styczeń, K., Datka, W., & Koperny, M. (2017). Vortioxetine: A review of the pharmacology and clinical profile of the novel antidepressant. Pharmacological Reports, 69(4), 595–601. https://doi.org/10.1016/j.pharep.2017.01.030
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22. Siwek, M., Chrobak, A. A., Gorostowicz, A., Krupa, A. J., & Dudek, D. (2021). Withdrawal Symptoms Following Discontinuation of Vortioxetine—Retrospective Chart Review. Pharmaceuticals, 14(5), 451. https://doi.org/10.3390/ph14050451
23. Jacobsen, P. L., Mahableshwarkar, A. R., Chen, Y., Chrones, L., & Clayton, A. H. (2015). Effect of Vortioxetine vs. Escitalopram on Sexual Functioning in Adults with Well-Treated Major Depressive Disorder Experiencing SSRI-Induced Sexual Dysfunction. The Journal of Sexual Medicine, 12(10), 2036–2048. https://doi.org/10.1111/jsm.12980
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