What is vortioxetine?

What is Vortioxetine?

Vortioxetine (brand name TRINTELLIX) is a second-generation antidepressant approved by the FDA for treating major depressive disorder in adults, distinguished by its multimodal mechanism of action that combines serotonin reuptake inhibition with direct effects on multiple serotonin receptor subtypes. 1

Mechanism of Action

Vortioxetine works through multiple complementary mechanisms that differentiate it from traditional SSRIs 1, 2:

• Serotonin transporter inhibition: Binds with high affinity (Ki=1.6 nM) and potently inhibits serotonin reuptake (IC50=5.4 nM) 1
• 5-HT3 receptor antagonism: Blocks 5-HT3 receptors (Ki=3.7 nM) 1, 2
• 5-HT1A receptor agonism: Activates 5-HT1A receptors (Ki=15 nM) 1, 2
• 5-HT7 receptor antagonism: Blocks 5-HT7 receptors (Ki=19 nM) 1
• 5-HT1B receptor partial agonism: Partially activates 5-HT1B receptors (Ki=33 nM) 1
• 5-HT1D receptor antagonism: Blocks 5-HT1D receptors (Ki=54 nM) 1

The antidepressant effect is thought to result from enhanced serotonergic activity in the CNS, though the specific contribution of each receptor interaction remains incompletely understood 1, 2.

Clinical Pharmacology

Dosing and Administration

• Starting dose: 10 mg orally once daily 1, 2
• Dose range: 5-20 mg daily 1, 2
• Administration: Can be taken without regard to food 1, 3
• Time to steady state: Approximately 2 weeks 3
• Half-life: Mean terminal half-life of approximately 66 hours 3

Pharmacokinetic Properties

• Bioavailability: 75% oral bioavailability 3
• Metabolism: Primarily via CYP2D6, with subsequent glucuronidation by UGT enzymes 1, 3
• Active metabolites: The major metabolite is pharmacologically inactive; minor active metabolites do not cross the blood-brain barrier, making the parent compound responsible for clinical effects 3
• Linear kinetics: Dose-proportional pharmacokinetics across the therapeutic range 3

Dose Adjustments Required

CYP2D6 poor metabolizers: Reduce dose by half (maximum 10 mg daily) due to higher plasma concentrations 1, 3

No dose adjustment needed for 1, 3:

• Age (including elderly patients ≥65 years)
• Sex
• Race
• Body size
• Renal impairment
• Hepatic impairment

Clinical Efficacy in Major Depressive Disorder

First-Line Treatment

Vortioxetine is recognized as a second-generation antidepressant option for initial treatment of MDD 4:

• Response rates: 53.2% with vortioxetine vs 35.2% with placebo in short-term studies 5
• Remission rates: 29.2% with vortioxetine vs 19.3% with placebo 5
• Long-term efficacy: Superior to placebo in preventing relapses and recurrences over 52 weeks 5

Second-Line Treatment

When used as a switch strategy after inadequate response to initial SSRI/SNRI treatment 4:

• Comparable efficacy: No significant differences between switching to vortioxetine versus other second-generation antidepressants (bupropion SR, escitalopram, duloxetine, sertraline, venlafaxine ER) 4
• Superior to agomelatine: Better improvement in depressive symptoms, response, and remission rates when switching from failed SSRI/SNRI 5

Cognitive Effects

Vortioxetine demonstrates unique procognitive properties that distinguish it from other antidepressants 2, 6, 7:

• Improves cognitive function in adults with severe depression independent of effects on mood symptoms 6
• Enhances visual and spatial memory, synaptic transmission, and neuroplasticity in preclinical models 6
• May exert stronger direct effects on cognitive function (assessed by DSST) than duloxetine 6
• Beneficial effects on memory, executive functioning, and attention documented in clinical trials 7, 5

Safety and Tolerability Profile

Common Adverse Effects

The most frequently reported side effects are 1, 7, 5:

• Nausea (most common, typically mild to moderate and transient)
• Vomiting
• Constipation
• Dizziness
• Diarrhea
• Headache (mostly transient)

Serious Adverse Events

Serotonin syndrome risk: Can occur, particularly when combined with other serotonergic drugs; one case reported with overdose >80 mg 1

Seizures: One case reported with overdose >80 mg 1

Hyponatremia: Serotonergic antidepressants carry this risk, particularly in elderly patients 1

Suicidality: Like all antidepressants, carries FDA black box warning for increased risk of suicidal thinking and behavior in children, adolescents, and young adults 1

Sexual Dysfunction

Vortioxetine may be beneficial for patients experiencing sexual dysfunction from other antidepressants, as it appears to have a more favorable sexual side effect profile than traditional SSRIs 6

Drug Interactions

Significant Interactions Requiring Dose Adjustment

Strong CYP2D6 inhibitors (e.g., bupropion, fluoxetine, paroxetine, quinidine) 1, 3:

• Reduce vortioxetine dose by half when co-administered
• Increase back to original dose when inhibitor discontinued

Strong CYP inducers (e.g., rifampin, carbamazepine, phenytoin) 1, 3:

• Consider increasing vortioxetine dose (maximum 3 times the original dose)
• Reduce to original dose when inducer discontinued

Minimal Interaction Risk

No clinically meaningful interactions with most other medications, including 3:

• Other antidepressants (except bupropion)
• Benzodiazepines
• Lithium
• Oral contraceptives
• Warfarin

Overdose Management

Reported overdose experience 1:

• Doses up to 40 mg: Increased nausea, dizziness, diarrhea, abdominal discomfort, pruritus, somnolence, flushing
• Doses 40-80 mg: Similar symptoms with nausea and vomiting most common
• Doses >80 mg: Risk of serotonin syndrome (when combined with other serotonergic drugs) and seizures

Management: No specific antidote exists; contact Poison Control (1-800-222-1222) or medical toxicologist for guidance 1

Clinical Positioning

When to Consider Vortioxetine

First-line option when 6, 7, 5:

• Cognitive symptoms are prominent features of depression
• Patient has failed other SSRIs/SNRIs due to sexual dysfunction
• Patient requires once-daily dosing with favorable tolerability

Second-line option when 4, 5:

• Initial SSRI/SNRI treatment fails to achieve remission
• Switching strategies are preferred over augmentation

Current Limitations

Cost considerations: More expensive than generic SSRIs, which may limit first-line use 7

Limited long-term data: Fewer large-scale, long-term clinical trials compared to established SSRIs 7

Not studied in certain populations: Limited data in pediatric patients, pregnant women, and patients with severe medical comorbidities 1

Comparative Context Among Antidepressants

The American College of Physicians guidelines establish that second-generation antidepressants, including vortioxetine, show no clinically significant differences in overall efficacy for acute-phase MDD 4. However, vortioxetine's unique multimodal mechanism and procognitive effects may provide advantages in specific clinical scenarios, particularly when cognitive dysfunction is a prominent feature of depression 2, 6, 7.