Vortioxetine
Multimodal antidepressant: SERT inhibitor + 5HT1A agonist + 5HT1B partial agonist + 5HT3/5HT7 antagonist
Vortioxetine
Trintellix (US), Brintellix (formerly)
Vortioxetine (brand name Trintellix in the US, formerly Brintellix) is a multimodal antidepressant FDA-approved in 2013 for major depressive disorder. Beyond SERT inhibition, it directly modulates multiple serotonin receptor subtypes: 5HT1A agonism, 5HT1B partial agonism, and 5HT3, 5HT7, and 5HT1D antagonism. This combination produces, via disinhibition, downstream increases in not only serotonin but also norepinephrine, dopamine, acetylcholine, histamine, and glutamate — the hypothesized basis for its pro-cognitive effects (improved processing speed) that have distinguished it in trials of MDD with cognitive symptoms.
The ondansetron-like 5HT3 antagonism reduces the GI side effects common to pure SSRIs (less nausea than typical SERT inhibitors). Sexual side effects appear to be lower than with SSRIs but still occur.
SERT inhibition + 5HT1A agonism + 5HT1B partial agonism + 5HT3, 5HT7, 5HT1D antagonism. The 5HT3 antagonism (similar to ondansetron) may underlie reduced GI side effects. The 5HT7 antagonism may underlie pro-cognitive effects.
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Effects
Nausea (most common; less than typical SSRIs), constipation, vomiting, sexual dysfunction (less than SSRIs but present). Lower rate of discontinuation symptoms due to long half-life.
Pharmacodynamics
Interactions
Pharmacogenomic + mechanism interactions
Pharmacogenomic guideline recommendationsCPIC and Dutch Pharmacogenetics Working Group clinical guidelines
CPIC rec 8095308 [Strong]: Initiate therapy with recommended starting dose. CPIC pair-level A (CYP2D6, CYP2C19, CYP2B6, SLC6A4, HTR2A and Serotonin Reuptake Inhibitor Antidepressants) [PMID 37032427]
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CPIC rec 8095315 [Moderate]: Initiate 50% of starting dose (e.g., 5 mg) and titrate to the maximum recommended dose of 10 mg or consider a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2D6. CPIC pair-level A (CYP2D6, CYP2C19, CYP2B6, SLC6A4, HTR2A and Serotonin Reuptake Inhibitor Antidepressants) [PMID 37032427] FDA labeling (Dosage and Administration, Clinical Pharmacology)
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CPIC rec 8095312 [Moderate]: Initiate therapy with recommended starting dose. CPIC pair-level A (CYP2D6, CYP2C19, CYP2B6, SLC6A4, HTR2A and Serotonin Reuptake Inhibitor Antidepressants) [PMID 37032427]
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CPIC rec 8095295 [Optional]: Select alternative drug not predominantly metabolized by CYP2D6. If vortioxetine use is warranted, initiate therapy at standard starting dose and titrate to maintenance dose based on efficacy and side effects. Increasing the target maintenance dose by 50% or more may be needed for efficacy. CPIC pair-level A (CYP2D6, CYP2C19, CYP2B6, SLC6A4, HTR2A and Serotonin Reuptake Inhibitor Antidepressants) [PMID 37032427] FDA labeling (Dosage and Administration, Clinical Pharmacology)
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Patient experience
Fluoxetine via Category:Antidepressants exp n/a/5 outcome n/a (n=1) exp 1.0/5 outcome +33.0 (n=1)
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Summary
Classes
Multimodal antidepressant: SERT inhibitor + 5HT1A agonist + 5HT1B partial agonist + 5HT3/5HT7 antagonist
Common uses
Major depressive disorder in adults (FDA-approved 2013). Notable for evidence of cognitive benefit (processing speed) that distinguishes it from other antidepressants.
Pharmacy
Starting dose
10 mg PO once daily; may increase to 20 mg as tolerated, or decrease to 5 mg if needed
Preparations
5 mg, 10 mg, 20 mg tablets
US FDA Max
20 mg/d
Pharmacology
Routes
Oral
Onset
Typical antidepressant 4-6 week onset
Duration
Daily dosing
Half-life
~66 hours
Bioavailability
~75%
Pregnancy
Limited data; weigh benefits/risks
Legal status
Rx
Purported mechanism
Sometimes called a 'serotonin modulator and stimulator.' Combines: SERT inhibition (raises 5-HT) + direct 5HT1A receptor agonism + 5HT1B partial agonism (heteroreceptor) + 5HT3, 5HT7, 5HT1D antagonism. Net effect: increased 5-HT, NE, DA, ACh, histamine, glutamate via disinhibition of multiple downstream circuits. Stahl emphasizes the 5HT3 antagonism + 5HT7 antagonism for the pro-cognitive effects.