What is the recommended treatment and dosage for major depressive disorder using Auvelity (dextromethorphan and bupropion)?

Auvelity for Major Depressive Disorder

Auvelity (dextromethorphan 45 mg/bupropion 105 mg) is FDA-approved for treating major depressive disorder in adults, with dosing starting at one tablet once daily for 3 days, then increasing to one tablet twice daily (morning and evening, at least 8 hours apart) as the maintenance dose. 1

Mechanism and Rationale

Auvelity combines two active components with complementary mechanisms:

• Dextromethorphan acts as an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist, modulating glutamatergic signaling 2, 3
• Bupropion serves dual purposes: it inhibits CYP2D6 to increase dextromethorphan bioavailability and provides additional antidepressant effects through norepinephrine-dopamine reuptake inhibition 2, 1

This pharmacokinetic and pharmacodynamic synergy accounts for the rapid onset of action observed in clinical trials 3.

Clinical Efficacy

Speed of Response

Auvelity demonstrates significantly faster antidepressant effects compared to conventional treatments, with measurable improvements in Montgomery-Åsberg Depression Rating Scale (MADRS) scores within 2 weeks 2. This rapid onset distinguishes it from traditional monoamine-based antidepressants that typically require 4-6 weeks for therapeutic effects.

Acute Treatment Outcomes

Phase 3 trial data showed:

• Significant reductions in MADRS total scores compared to placebo 2
• Superior efficacy versus bupropion monotherapy in head-to-head comparison 2
• Higher remission and response rates compared to both placebo and bupropion alone 2

Long-Term Effectiveness

Two open-label extension studies demonstrated sustained benefits:

• Remission rates approached 70% with continued treatment 2
• Response rates exceeded 80% through 12-15 months of treatment 2
• Large reductions in MADRS scores were maintained throughout the study duration 2

Treatment Positioning

First-Line Use

Auvelity can be initiated as first-line monotherapy for MDD 4. Real-world data shows that 10.1% of patients initiated Auvelity without prior antidepressant treatment in the preceding 12 months 5.

Second-Line and Treatment-Resistant Depression

Auvelity is particularly valuable when patients fail to achieve remission with serotonin-targeting agents (SSRIs/SNRIs) 4. In real-world practice:

• 83.7% of patients had previously received SSRIs (54.9%), bupropion (40.4%), and/or SNRIs (35.9%) 5
• 28.8% initiated Auvelity as monotherapy while 71.2% used it as add-on therapy 5
• Most commonly added to SSRI monotherapy (10.7%) or SNRI monotherapy (6.5%) 5

Safety and Tolerability

Auvelity was well-tolerated in clinical trials, with most adverse events rated as mild-to-moderate 2. The combination demonstrated:

• Lower discontinuation rates due to adverse events compared to some alternatives 2
• Favorable tolerability profile maintained through long-term treatment 2

Key Advantage Over Other Antidepressants

Bupropion is associated with lower rates of sexual adverse events compared to fluoxetine and sertraline 6, making Auvelity an attractive option for patients concerned about sexual dysfunction—a common reason for antidepressant discontinuation.

Clinical Context

While the American College of Physicians recommends selecting between cognitive behavioral therapy (CBT) or second-generation antidepressants for MDD 6, Auvelity represents a mechanistically distinct option that targets glutamatergic rather than purely monoaminergic systems. This is particularly relevant given that:

• Bupropion shows comparable efficacy to other SGAs when switching treatments 6
• Augmenting with bupropion decreases depression severity more than buspirone 6
• The glutamatergic mechanism offers an alternative for patients who have not responded to conventional monoamine-based treatments 3

Practical Implementation

Start with one tablet (dextromethorphan 45 mg/bupropion 105 mg) once daily for the first 3 days, then advance to the maintenance dose of one tablet twice daily (morning and evening, separated by at least 8 hours) 1. This titration schedule balances rapid therapeutic onset with tolerability.

The medication's familiarity to clinicians (both components are well-established agents) increases acceptability and confidence in prescribing 4, while the novel combination provides mechanistic innovation for patients requiring alternatives to traditional antidepressants.