What is Trintellix (vortioxetine) used for?

Trintellix (Vortioxetine) Overview

Trintellix (vortioxetine) is FDA-approved for the treatment of major depressive disorder (MDD) in adults, with a unique multimodal mechanism that distinguishes it from traditional SSRIs and SNRIs. 1

Indications and Approved Use

• Primary indication: Treatment of major depressive disorder in adults 1
• Not approved for use in pediatric patients 1

Mechanism of Action

Vortioxetine has a distinctive multimodal pharmacological profile that sets it apart from conventional antidepressants:

• High affinity for serotonin transporter (SERT) with reuptake inhibition 2
• 5-HT3 receptor antagonist activity 2
• 5-HT7 receptor antagonist activity 2
• 5-HT1A receptor agonist activity 2
• This combination of receptor modulation and SERT inhibition creates effects beyond simple serotonin reuptake inhibition 2, 3

Dosing and Administration

Starting dose: 10 mg orally once daily without regard to meals 1

Titration strategy:

• Increase to 20 mg/day as tolerated for optimal efficacy 1
• May decrease to 5 mg/day for patients who cannot tolerate higher doses 1
• Maximum studied dose is 20 mg/day 1

Special populations requiring dose adjustment:

• CYP2D6 poor metabolizers: Maximum dose 10 mg/day 1
• Patients on strong CYP2D6 inhibitors (bupropion, fluoxetine, paroxetine, quinidine): Reduce dose by one-half 1
• Patients on strong CYP inducers (rifampin, carbamazepine, phenytoin) for >14 days: Consider increasing dose up to 3 times original dose 1

Pharmacokinetics

• Bioavailability: 75% oral absorption 4
• Half-life: Approximately 66 hours, allowing once-daily dosing 4
• Time to steady state: Generally achieved within 2 weeks 4
• Metabolism: Via CYP450 enzymes (primarily CYP2D6) and UGT glucuronidation 4
• Active metabolites: Major metabolite is pharmacologically inactive; minor active metabolite does not cross blood-brain barrier 4
• No clinically significant effects from sex, age, race, body size, or renal/hepatic function on drug exposure 4

Clinical Efficacy

Compared to placebo:

• Superior response rates (RR 1.35,95% CI 1.23-1.48) 5
• Superior remission rates (RR 1.33,95% CI 1.17-1.52) 5
• Improved cognitive function (SMD 0.34,95% CI 0.16-0.52) 5

Compared to other antidepressants:

• Similar efficacy to SNRIs in response and remission rates 5
• Better tolerability than SNRIs (RR 0.90,95% CI 0.86-0.94) 5
• Comparable efficacy to SSRIs 5
• As effective as venlafaxine and more efficient than agomelatine in MDD treatment 3

Unique Cognitive Benefits

Vortioxetine demonstrates procognitive effects that distinguish it from traditional antidepressants:

• Improves synaptic transmission and neuroplasticity in hippocampal pyramidal cells responsible for memory and learning 3
• Enhances visual and spatial memory in preclinical models 3
• First antidepressant to efficiently augment cognitive function in adults with severe depression, independent of its effects on mood 3
• May exert stronger direct effects on cognitive functions (assessed with DSST) than duloxetine 3

Treatment Duration

For first episode of MDD: Continue treatment for 4-9 months after satisfactory response 6

For recurrent depression (≥2 episodes): Consider even longer duration of therapy 6

Discontinuation

Recommended tapering approach:

• For patients on 15-20 mg/day: Decrease to 10 mg/day for one week before full discontinuation 1
• Abrupt discontinuation can cause transient adverse reactions including headache and muscle tension 1

Adverse Effects Profile

Most common side effects:

• Nausea (most prevalent, typically mild to moderate and often transient) 3, 7
• Vomiting 7
• Constipation 7
• Headache (mostly transient) 3

Sexual dysfunction: May actually help overcome sexual dysfunction caused by other antidepressants 3

Tolerability: Generally well tolerated with favorable safety profile compared to many other antidepressants 2, 3

Critical Safety Warnings

BLACK BOX WARNING: Increased risk of suicidal thoughts and behavior in pediatric and young adult patients 1

• Close monitoring required for clinical worsening and emergence of suicidal thoughts/behaviors in all antidepressant-treated patients 1
• Screen for personal or family history of bipolar disorder, mania, or hypomania before initiating treatment 1

Drug Interactions and Contraindications

MAOI interactions:

• Wait 14 days after discontinuing MAOI before starting vortioxetine 1
• Wait 21 days after stopping vortioxetine before starting MAOI 1
• Risk of serotonin syndrome with concurrent use 1

Significant CYP interactions requiring dose adjustment:

• Strong CYP2D6 inhibitors (bupropion, fluoxetine, paroxetine, quinidine) 1
• Strong CYP inducers (rifampin, carbamazepine, phenytoin) 1

Similar Medications

Most similar alternative: Vilazodone, which combines SSRI action with 5-HT1A receptor partial agonism 8

Consider vilazodone as first alternative when:

• Cognitive symptoms are prominent 8
• Sexual dysfunction is a concern 8

Other alternatives:

• Bupropion for sexual dysfunction concerns 8
• Desvenlafaxine (SNRI without receptor modulation) 8

Clinical Positioning

Vortioxetine represents a good second-line antidepressant option with potential to become first-line pending additional long-term data 7. Its unique procognitive properties make it particularly valuable for patients with MDD who have prominent cognitive symptoms 2, 3. The main disadvantages are cost and limited long-term efficacy data from large clinical trials 7.