What is the recommended adult dosing of Trintellix (vortioxetine) for major depressive disorder, including adjustments for strong CYP2D6 inhibitors, moderate hepatic impairment, age, and renal function?

Trintellix (Vortioxetine) Dosing for Major Depressive Disorder

Standard Adult Dosing

The recommended starting dose of Trintellix is 10 mg once daily, with a target therapeutic dose of 20 mg once daily for optimal efficacy in the United States. 1

• Initial dose: 10 mg once daily, taken orally without regard to food 1, 2
• Target dose: Increase to 20 mg once daily if the 10 mg dose is tolerated, as 20 mg/day was the effective dose demonstrated in US clinical trials 1
• Lower dose option: 5 mg once daily can be considered for patients who do not tolerate higher doses 1
• Dose range: The approved therapeutic range is 5-20 mg once daily 1, 3, 2

Time to Steady State and Response

• Steady-state plasma concentrations are achieved within approximately 2 weeks of once-daily dosing due to vortioxetine's mean terminal half-life of 66 hours 2
• The pharmacokinetics are linear and dose-proportional across the therapeutic range 2

Dose Adjustments for Drug Interactions

Strong CYP2D6 Inhibitors (e.g., Bupropion, Fluoxetine, Paroxetine, Quinidine)

Reduce the maximum vortioxetine dose to 10 mg once daily when co-administered with strong CYP2D6 inhibitors. 1, 2

• This is the only drug interaction requiring mandatory dose adjustment 2
• CYP2D6 poor metabolizers should also have a maximum dose of 10 mg once daily 1

CYP Inducers (e.g., Rifampin)

• Strong CYP inducers like rifampin significantly reduce vortioxetine exposure and may require dose adjustment, though specific recommendations are not established 2
• Consider increasing the vortioxetine dose if clinically indicated when co-administered with broad CYP inducers 2

Special Populations

Age

No dose adjustment is required based on age alone. 4, 1

• Elderly patients showed no clinically meaningful differences in vortioxetine exposure compared to younger adults 4
• The exposure difference was within the 50%-200% range considered clinically acceptable 4

Renal Impairment

No dose adjustment is necessary for any degree of renal impairment. 4, 1

• Studies demonstrated no clinically meaningful differences in vortioxetine exposure across varying degrees of renal function 4

Hepatic Impairment

No dose adjustment is required for mild to moderate hepatic impairment. 4, 1

• Vortioxetine exposure remained within acceptable limits in patients with hepatic impairment 4
• Severe hepatic impairment has not been adequately studied; use caution in this population 4

Sex and Race

No dose adjustments are needed based on sex or race. 4, 1

• No clinically meaningful differences were observed between men and women or among different racial groups 4

Maintenance Dosing

For patients achieving remission on 10 mg daily, all doses (5 mg, 10 mg, and 20 mg) are effective for relapse prevention. 5

• In the RESET study, vortioxetine 5 mg (19.3% relapse), 10 mg (17.9% relapse), and 20 mg (17.4% relapse) all significantly reduced relapse risk compared to placebo (32.5% relapse) over 28 weeks 5
• The maintenance dose should be determined by clinical judgment, considering the dose on which the patient achieved remission and tolerability 1
• A US maintenance dose-response study covering the approved dose range has been requested by the FDA 1

Discontinuation

Vortioxetine can be discontinued abruptly without tapering for doses of 10 mg daily or less. 1

• For doses of 15 mg or 20 mg daily, reduce to 10 mg daily for 1 week prior to full discontinuation to minimize potential withdrawal symptoms 1
• The long half-life (approximately 66 hours) provides some inherent protection against withdrawal 2

Clinical Considerations

Common Pitfalls

• Underdosing in US patients: The effective dose in US trials was 20 mg daily, whereas lower doses (5-10 mg) were effective in non-US studies 1. Don't settle for 10 mg if the patient tolerates higher doses and hasn't achieved adequate response.
• Forgetting CYP2D6 interactions: Always check for strong CYP2D6 inhibitors (especially bupropion, which is commonly co-prescribed) and reduce the maximum dose to 10 mg daily 1, 2
• Premature discontinuation due to nausea: Nausea is the most common adverse event and is dose-dependent 1. Consider temporary dose reduction or symptomatic management rather than discontinuation.

Tolerability Profile

• Nausea is the most common adverse event and is dose-dependent 1
• Sexual dysfunction may occur at higher doses but appears less common than with traditional SSRIs 1
• Low risk of weight gain and sedation compared to other antidepressants 3
• Overall adverse event profile is similar to SSRIs 1