What are the dosing guidelines, contraindications, adverse effects, drug interactions, and monitoring recommendations for vortioxetine in adults with major depressive disorder?

Vortioxetine for Major Depressive Disorder

Dosing Guidelines

Vortioxetine should be initiated at 10 mg orally once daily, with a therapeutic dose range of 5-20 mg daily, administered without regard to food. 1, 2

• The recommended starting dose is 10 mg once daily 1
• Dose range: 5-20 mg daily 1, 3
• Administration: Once daily, without need for food 1, 2
• Time to steady state: Approximately 14 days (mean terminal half-life ~66 hours) 3, 2
• Oral bioavailability: 75% 2

Dose Adjustments

Reduce the dose in CYP2D6 poor metabolizers, as this is the only population requiring routine dose adjustment. 2

• CYP2D6 poor metabolizers: Dose reduction recommended 2
• Strong CYP2D6 inhibitors (e.g., bupropion): Consider dose reduction 2
• Broad CYP inducers (e.g., rifampin): May require dose increase 2
• No dose adjustment needed for: sex, age, race, body size, renal impairment, or hepatic impairment 2

Treatment Duration

Continue vortioxetine for 4-9 months after achieving satisfactory response in first-episode depression, and for longer duration in recurrent depression. 4, 5

• First episode MDD: Continue for 4-9 months after response 4, 5
• Recurrent depression: Continue for longer than 9 months 4, 5
• Treatment-resistant depression: If vortioxetine achieves clinical stability after multiple prior failures, maintain the current dose rather than discontinue to avoid relapse 4

Monitoring Recommendations

Assess therapeutic response and adverse effects within 1-2 weeks of initiating or modifying vortioxetine therapy. 4, 5

• Begin monitoring within 1-2 weeks of treatment initiation 4, 5
• Evaluate response at 6-8 weeks; modify treatment if inadequate response 5
• Continue regular assessment throughout treatment 4

Contraindications and Drug Interactions

Avoid combining vortioxetine with strong CYP2D6 inhibitors (particularly bupropion) and broad CYP inducers (rifampin) without dose adjustment. 2

Metabolism and Interactions

• Primary metabolism: CYP2D6 and CYP3A4/5, followed by UGT conjugation 3, 2
• Bupropion (strong CYP2D6 inhibitor): Clinically significant interaction requiring dose adjustment 2
• Rifampin (broad CYP inducer): Clinically significant interaction requiring dose adjustment 2
• Other evaluated drugs: No clinically meaningful interactions observed 2

Important Caveat

The major metabolite is pharmacologically inactive, and the minor active metabolite does not cross the blood-brain barrier, making the parent compound primarily responsible for therapeutic effects 2

Adverse Effects

Nausea is the most common adverse effect, followed by constipation and vomiting; sexual dysfunction may occur at higher doses but weight gain and sedation risk are low. 3, 6

Common Adverse Effects

• Most prevalent: Nausea (mild to moderate, often transient) 7, 3
• Other common: Constipation, vomiting, headaches (mostly transient) 7, 3
• Sexual dysfunction: May occur at higher doses 7, 3
• Low risk: Weight gain and sedation 3

Overall Safety Profile

• Patients on vortioxetine reported more adverse events than placebo (OR = 1.21; 95% CI, 1.06-1.38) 6
• Generally well tolerated with mostly mild to moderate side effects 7
• Fairly benign safety and tolerability profile compared to other antidepressants 1

Clinical Positioning and Selection

Select vortioxetine after discussing adverse effect profiles, cost, accessibility, and patient preferences, as second-generation antidepressants show similar efficacy to each other and to cognitive behavioral therapy. 8, 9

Evidence-Based Positioning

• No established superiority of one second-generation antidepressant over another in response or remission rates 4, 9
• Similar efficacy to cognitive behavioral therapy for MDD 8, 9
• Selection should be based on adverse effect profile, cost, and patient preferences rather than efficacy differences 8, 4

Unique Characteristics

• Multimodal mechanism: SERT inhibitor, 5-HT3 and 5-HT7 antagonist, 5-HT1A agonist 1, 7
• Procognitive effects: May improve cognitive function in MDD patients, potentially superior to other antidepressants 7
• Efficacy comparable to venlafaxine and more efficient than agomelatine 7

When to Consider Vortioxetine

• Treatment-resistant depression: Appropriate after failure of at least two antidepressants with different mechanisms 4
• Cognitive dysfunction in depression: May be particularly beneficial given procognitive properties 7
• Sexual dysfunction from prior antidepressants: May help overcome this adverse effect 7
• Patients requiring low sedation/weight gain risk: Favorable profile compared to many alternatives 3

Clinical Considerations

Cognitive behavioral therapy should be strongly considered as an alternative to vortioxetine where accessible, as it shows similar efficacy with fewer adverse effects and lower relapse rates. 8, 9

• CBT has similar efficacy to second-generation antidepressants 8, 9
• CBT demonstrates lower relapse rates than antidepressants 8, 9
• CBT has fewer adverse effects than pharmacotherapy 8, 9
• Where CBT is accessible, it should be strongly considered as an alternative 9