What is the recommended treatment and dosage of Auvelity (dextromethorphan-bupropion) for an adult patient with major depressive disorder?

Auvelity for Major Depressive Disorder

Recommended Dosing and Treatment Approach

Start Auvelity at 45 mg dextromethorphan/105 mg bupropion once daily in the morning for 3 days, then increase to the target dose of 45 mg/105 mg twice daily (morning and evening, at least 8 hours apart). 1, 2

Initial Dosing Schedule

• Days 1-3: One tablet (45 mg/105 mg) once daily in the morning 1
• Day 4 onward: One tablet twice daily (total daily dose: 90 mg dextromethorphan/210 mg bupropion) 1, 2
• Tablets must be swallowed whole; do not crush, divide, or chew 3
• May be taken with or without food 3

When to Use Auvelity

Auvelity can be initiated as first-line monotherapy, as second-line treatment after SSRI/SNRI failure, or as add-on therapy to existing antidepressants. 4 Real-world data shows 28.8% of patients use it as monotherapy, while 71.2% add it to existing treatment, most commonly SSRIs (10.7%) or SNRIs (6.5%) 4.

The American College of Physicians recommends discussing treatment effects, adverse effect profiles, cost, accessibility, and patient preferences when selecting antidepressants, with cognitive behavioral therapy being equally effective and potentially having fewer adverse effects than pharmacotherapy 5.

Expected Timeline for Response

Expect significant symptom improvement within 1-2 weeks, which is notably faster than traditional antidepressants 1. Phase 2 and 3 trials demonstrated statistically significant reductions in Montgomery-Åsberg Depression Rating Scale scores compared to placebo and bupropion monotherapy by week 2 1. Response rates exceeded 80% and remission rates approached 70% in long-term studies extending to 12-15 months 1.

Critical Safety Considerations

Absolute Contraindications

• Do not use within 14 days of MAOI discontinuation or initiation 3
• Do not use in patients with seizure disorders or conditions that increase seizure risk 3, 6
• Do not use in patients with current or prior diagnosis of bulimia or anorexia nervosa (increased seizure risk) 3
• Do not use during abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs 3

Boxed Warning

Monitor closely for suicidal thoughts and behaviors, particularly in patients under age 25 during the first 1-2 months of treatment. 3, 6 This applies to all antidepressants, including Auvelity.

Most Common Adverse Effects (Mild-to-Moderate)

• Dizziness, nausea, headache, diarrhea 1, 6
• Somnolence, dry mouth, hyperhidrosis 6
• Sexual dysfunction, anxiety, constipation, decreased appetite, insomnia 6

Notably, bupropion-containing regimens have significantly lower rates of sexual dysfunction compared to SSRIs like fluoxetine, sertraline, or paroxetine 5, making Auvelity advantageous when sexual side effects are a concern.

Dose Adjustments for Special Populations

Hepatic Impairment

• Moderate to severe (Child-Pugh 7-15): Maximum dose is 45 mg/105 mg every other day 3
• Mild (Child-Pugh 5-6): Consider reducing dose and/or frequency 3

Renal Impairment

• GFR <90 mL/min: Consider reducing dose and/or frequency 3

Mechanism and Rationale

Auvelity combines two complementary mechanisms: dextromethorphan acts as an NMDA receptor antagonist and sigma-1 receptor agonist (modulating glutamate signaling), while bupropion inhibits CYP2D6 to increase dextromethorphan bioavailability by approximately 20-fold and provides additional norepinephrine-dopamine reuptake inhibition 1, 2. This represents a mechanistically novel approach targeting glutamatergic pathways rather than solely monoaminergic systems 7.

Clinical Pitfalls to Avoid

• Do not assume all augmentation strategies are equivalent: When augmenting existing therapy, bupropion-based strategies outperform buspirone for depression severity reduction 8, 9
• Do not overlook drug interactions: Bupropion induces CYP3A4, potentially reducing efficacy of oral contraceptives and immunosuppressants 5
• Do not wait indefinitely for response: If inadequate response occurs by 6-8 weeks, modify treatment strategy 9
• Do not use with linezolid or IV methylene blue without stopping Auvelity first due to hypertensive reaction risk 3