Mechanism of Action of Vortioxetine

Introduction

Vortioxetine is a multimodal antidepressant approved for major depressive disorder (MDD). It uniquely combines serotonin transporter (SERT) inhibition with agonist, partial agonist, and antagonist actions at various serotonin receptors, enhancing efficacy on mood, cognition, and anxiety.

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Step-by-Step Mechanism of Action

1. Inhibition of SERT
   Vortioxetine blocks the serotonin transporter, increasing extracellular serotonin levels.
2. Direct receptor modulation
   • 5‑HT₁A receptor agonist: Enhances serotonergic tone and reduces anxiety
   • 5‑HT₁B partial agonist: Regulates serotonin release
   • 5‑HT₃ receptor antagonist: Reduces gastrointestinal side effects and modulates cortex function
   • 5‑HT₇ receptor antagonist: Improves cognitive processing and circadian modulation
3. Enhanced serotonergic neurotransmission
   Combined effects on transporter and receptors improve mood, anxiety, and cognitive domains.
4. Downstream neuroplastic effects
   Increased BDNF release and hippocampal neurogenesis contribute to sustained antidepressant effects.
5. Multimodal synergy
   Unique combination may provide faster cognitive improvement, fewer GI side effects, and better overall tolerability.

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Pharmacokinetic Parameters

Parameter	Value
Route	Oral tablet, once daily
Bioavailability	~75–90%
Time to Peak (Tmax)	~7–11 hours
Protein Binding	~98–99%
Metabolism	CYP2D6 (major) and CYP3A4 (minor)
Half-life	~66 hours
Excretion	Metabolites in urine and feces

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Clinical Uses

• Major depressive disorder (MDD)
• Off-label use: generalized anxiety, cognitive symptoms in depression

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Adverse Effects

• Nausea (most common)
• Sexual dysfunction
• Headache and dizziness
• Rare: hyponatremia, hypersensitivity
• Low discontinuation rates due to mild side effect profile

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Comparative Analysis

Agent	Mood Effect	Cognitive Benefit	Key Side Effects
Vortioxetine	Yes	Significant	Low GI, mild sexual issues
Sertraline	Yes	Mild	High GI, sexual dysfunction
Duloxetine	Yes	Mild–moderate	Moderate GI, hypertension

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MCQs

1. Vortioxetine’s action includes:
   a) SERT inhibition only
   b) Receptor modulation only
   c) Both SERT inhibition and receptor modulation
   d) Dopamine transporter blockade
   Answer: c) Both SERT inhibition and receptor modulation
2. It acts as an agonist at which receptor?
   a) 5‑HT₁A
   b) 5‑HT₃
   c) 5‑HT₇
   d) 5‑HT₂C
   Answer: a) 5‑HT₁A
3. Receptor antagonism at 5‑HT₃ leads to:
   a) Enhanced GI side effects
   b) Fewer GI side effects
   c) More anxiety
   d) Worse cognition
   Answer: b) Fewer GI side effects
4. Which metabolism pathway is primary?
   a) CYP3A4
   b) CYP2D6
   c) UGT
   d) Renal excretion
   Answer: b) CYP2D6
5. Half-life is approximately:
   a) 8 hours
   b) 24 hours
   c) 66 hours
   d) 7 days
   Answer: c) 66 hours
6. Cognitive benefit compared to sertraline is:
   a) Similar
   b) Superior
   c) Inferior
   d) None
   Answer: b) Superior
7. Protein binding is around:
   a) 50%
   b) 75%
   c) >98%
   d) 100%
   Answer: c) >98%
8. Receptor partial agonism occurs at:
   a) 5‑HT₃
   b) 5‑HT₁B
   c) 5‑HT₇
   d) 5‑HT₂A
   Answer: b) 5‑HT₁B
9. Compared to duloxetine, vortioxetine side effects are:
   a) More severe
   b) Similar
   c) Milder
   d) Unknown
   Answer: c) Milder
10. Neuroplastic effects include:
    a) Dendritic pruning
    b) BDNF increase
    c) Dopamine decrease
    d) NMDA blockade
    Answer: b) BDNF increase

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FAQs

1. Does vortioxetine improve cognition?
Yes—studies show enhanced executive function and processing speed.

2. Is sexual dysfunction common?
Less common compared to SSRIs and SNRIs, but possible.

3. Can it cause serotonin syndrome?
Rarely, if combined with other serotonergic agents like MAO inhibitors or triptans.

4. Is dose adjustment needed in liver impairment?
Yes—lower dose (5 mg) is recommended in moderate hepatic impairment.

5. How long before effects manifest?
Some patients report mood improvement within 1–2 weeks; full benefit often by 6–8 weeks.

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References

• FDA Label: Vortioxetine
• DrugBank: Vortioxetine Summary
• StatPearls: Vortioxetine Pharmacology
• PubMed Review: Multimodal Mechanism and Cognitive Effects
• PMC Article: Vortioxetine and Neuroplasticity