What is the recommended treatment approach for an adult patient with a history of depression using Auvelity (dextromethadone/bupropion)?

Auvelity (Dextromethorphan-Bupropion) for Major Depressive Disorder

Direct Recommendation

Auvelity is an effective, FDA-approved treatment option for adults with major depressive disorder that can be used as either monotherapy or add-on therapy, with demonstrated rapid onset of antidepressant effects within 2 weeks and high remission rates approaching 70% in long-term studies. 1, 2

Clinical Context and Positioning

Auvelity represents a novel mechanism combining dextromethorphan (an NMDA receptor antagonist and sigma-1 receptor agonist) with bupropion (which increases dextromethorphan bioavailability through CYP2D6 inhibition). 1, 2 This combination received FDA approval in August 2022 for treating MDD in adults. 2

When to Consider Auvelity

First-line therapy scenarios:

• Can be initiated as monotherapy in treatment-naïve patients—real-world data shows 10.1% of patients started Auvelity without prior treatment in the preceding 12 months. 3
• Appropriate as initial pharmacotherapy alongside or instead of traditional second-generation antidepressants (SSRIs/SNRIs), consistent with ACP guidelines recommending second-generation antidepressants as first-line treatment. 4

Add-on therapy scenarios:

• Most commonly used as add-on treatment (71.2% of real-world patients), particularly when added to SSRIs (10.7% of cases) or SNRIs (6.5% of cases). 3
• Suitable for patients who have failed to achieve remission with serotonin-targeting agents. 5
• Appropriate for treatment-resistant depression after failure of two or more adequate antidepressant trials. 6, 5

Efficacy Profile

Rapid onset of action:

• Significant reductions in Montgomery-Åsberg Depression Rating Scale (MADRS) scores observed within 2 weeks, distinguishing it from traditional antidepressants that typically require 4-6 weeks. 1

Response and remission rates:

• Phase 3 trial demonstrated significant MADRS score reductions compared to placebo. 1
• Phase 2 trial showed superior efficacy versus bupropion monotherapy alone. 1
• Long-term studies (12-15 months) achieved remission rates approaching 70% and response rates exceeding 80%. 1

Safety and Tolerability

Critical safety warnings:

• Boxed warning: Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients, as with all antidepressants. 7
• Seizure risk increases at higher doses—monitor carefully and avoid in patients with seizure disorders. 7

Common adverse effects (generally mild-to-moderate):

• Dizziness, nausea, headache, diarrhea, somnolence 7
• Dry mouth, sexual dysfunction, hyperhidrosis 7
• Anxiety, constipation, decreased appetite, insomnia 7

Treatment Algorithm

Step 1: Patient selection

• Confirm MDD diagnosis using DSM-5 criteria (≥5 symptoms including depressed mood or anhedonia for ≥2 weeks affecting function). 6
• Assess severity using PHQ-9, HAM-D, or MADRS. 6
• Screen for seizure history, eating disorders, or abrupt alcohol/benzodiazepine discontinuation (contraindications to bupropion component). 7

Step 2: Initiation strategy

• Monotherapy approach: Start Auvelity in treatment-naïve patients or after discontinuing prior ineffective antidepressant (with appropriate washout period). 3, 5
• Add-on approach: Continue existing SSRI or SNRI and add Auvelity for augmentation—this reflects the most common real-world usage pattern. 3

Step 3: Monitoring schedule

• Assess response at 2 weeks (earlier than traditional 4-6 week timeline due to rapid onset). 1
• Monitor for suicidality, especially in first 1-2 weeks and in patients under age 25. 6, 7
• Evaluate therapeutic response using validated tools (≥50% reduction in severity scores indicates response). 6
• If inadequate response by 6-8 weeks, consider dose adjustment or treatment modification. 6

Step 4: Continuation phase

• Continue treatment for minimum 4-9 months after achieving satisfactory response for first episode. 6
• For recurrent depression, consider longer duration (≥1 year) or indefinite treatment at lowest effective dose. 8, 6

Real-World Usage Patterns

Analysis of 22,288 patients initiating Auvelity within one year of FDA approval revealed:

• Mean age 45.1 years, 68.1% women 3
• 53.5% had comorbid mental health disorders, with 47.6% having anxiety disorders 3
• 83.7% had prior treatment with SSRIs (54.9%), bupropion (40.4%), or SNRIs (35.9%) 3
• 28.8% initiated as monotherapy versus 71.2% as add-on therapy 3

Critical Pitfalls to Avoid

• Do not use in patients with seizure disorders or conditions that increase seizure risk—the bupropion component significantly elevates this risk. 7
• Do not combine with MAOIs or use within 14 days of MAOI discontinuation—risk of hypertensive crisis and serotonin syndrome. 7
• Do not assume standard antidepressant timeline—assess response at 2 weeks given rapid onset, but continue monitoring through 6-8 weeks. 1, 6
• Do not discontinue prematurely—maintain treatment for minimum 4-9 months after response to prevent relapse. 6
• Do not overlook suicidality monitoring—particularly critical in young adults despite approval only for adult use. 7

Comparison to Guideline-Recommended First-Line Agents

While ACP guidelines recommend choosing between cognitive behavioral therapy or second-generation antidepressants (SSRIs/SNRIs) as first-line treatment 4, Auvelity offers distinct advantages:

• Faster onset of action (2 weeks versus 4-6 weeks) 1
• Novel mechanism targeting glutamate signaling rather than monoamines alone 1, 2
• Higher long-term remission rates (approaching 70%) compared to typical SSRI remission rates (36%) 1, 8
• Effective as both monotherapy and augmentation strategy 3, 5

The medication represents a valuable addition to the treatment armamentarium, particularly for patients requiring rapid symptom relief or those who have not achieved remission with traditional serotonin-targeting agents. 1, 5