What is Auvelity (dextromethorphan-bupropion)?

What is Auvelity?

Auvelity is a novel FDA-approved medication for major depressive disorder (MDD) in adults that combines dextromethorphan hydrobromide and bupropion hydrochloride, working as an NMDA receptor antagonist and sigma-1 receptor agonist with a faster onset of action than traditional antidepressants. 1

Mechanism of Action and Composition

Auvelity represents a unique approach to treating depression through its dual-component formulation:

• Dextromethorphan: Functions as an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist, modulating glutamate signaling 1
• Bupropion: Serves two purposes:
  1. Acts as a norepinephrine-dopamine reuptake inhibitor (NDRI) with antidepressant properties 2
  2. Inhibits CYP2D6 enzymes, thereby increasing dextromethorphan's bioavailability 3

This combination creates both pharmacokinetic and pharmacodynamic synergy, which may explain its relatively rapid onset of action compared to traditional antidepressants 4.

Clinical Efficacy

Auvelity has demonstrated significant clinical benefits in treating MDD:

• Rapid onset: Significant reductions in depression scores (measured by Montgomery-Åsberg Depression Rating Scale) within two weeks of treatment initiation 1
• Superior efficacy: Phase 3 trials showed significantly greater improvement compared to placebo, and phase 2 trials demonstrated superiority over bupropion monotherapy 1
• High response rates: Long-term studies showed:
  • Remission rates approaching 70%
  • Response rates greater than 80%
  • Maintained efficacy through 12-15 months of treatment 1

Real-World Usage Patterns

Since its FDA approval in August 2022, Auvelity has been prescribed to over 22,000 patients with MDD in the United States, with the following patterns observed:

• Patient demographics: Mean age 45.1 years, 68.1% women 5
• Treatment approach:
  • 28.8% initiated as monotherapy
  • 71.2% added to existing treatments (most commonly to SSRIs or SNRIs)
  • 10.1% prescribed to treatment-naïve patients 5

Place in Treatment Algorithm

Auvelity can be considered in several clinical scenarios:

• As a first-line therapy for MDD
• As a second-line option when patients fail to achieve remission with serotonin-targeting agents
• For treatment-resistant depression 6

This aligns with the American College of Physicians guideline recommendation that clinicians select between cognitive behavioral therapy or second-generation antidepressants for MDD treatment after discussing effects, adverse profiles, cost, accessibility, and preferences with patients 7.

Safety and Tolerability

Auvelity is generally well-tolerated:

• Common adverse effects: Similar to those seen with bupropion, including insomnia, dry mouth, anxiety/jitteriness, decreased appetite, and headache 2, 1
• Monitoring requirements: Regular monitoring of blood pressure and heart rate is necessary, especially during the first 12 weeks of treatment 2
• Contraindications: Should be avoided in patients with:
  • Uncontrolled hypertension
  • History of seizures or conditions lowering seizure threshold
  • Current use of MAO inhibitors
  • Brain metastases or structural abnormalities
  • Current alcohol/substance abuse 2

Key Advantages Over Traditional Antidepressants

Auvelity offers several potential advantages:

1. Novel mechanism: Targets glutamatergic signaling rather than solely focusing on monoamine pathways 1, 4
2. Faster onset: May provide relief more quickly than traditional antidepressants 1
3. Different side effect profile: May be better tolerated than some other antidepressant options 1
4. High remission rates: Demonstrated ability to achieve remission in a large percentage of patients 1

Auvelity represents an important addition to the antidepressant armamentarium, offering a mechanistically novel approach with promising efficacy and tolerability for adults with MDD.