What is Auvelity (dextromethorphan and bupropion)?

What is Auvelity?

Auvelity is an FDA-approved oral medication combining dextromethorphan hydrobromide (45 mg) and bupropion hydrochloride (105 mg) for the treatment of major depressive disorder in adults, approved in August 2022. 1

Mechanism of Action

Auvelity works through a dual mechanism that distinguishes it from traditional antidepressants:

• Dextromethorphan acts as an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist, modulating glutamate signaling rather than targeting monoamine systems 2, 1
• Bupropion serves two roles: it inhibits CYP2D6 to increase dextromethorphan bioavailability by preventing its rapid metabolism, and it acts as a norepinephrine-dopamine reuptake inhibitor with independent antidepressant effects 2, 1

Clinical Efficacy

The medication demonstrates rapid onset of antidepressant effects, with significant improvements seen within 2 weeks of treatment initiation. 2

Key Trial Results:

• Phase 3 trial: Patients taking dextromethorphan-bupropion 45-105 mg showed significant reductions in Montgomery-Åsberg Depression Rating Scale (MADRS) scores compared to placebo 2
• Phase 2 trial: Dextromethorphan-bupropion demonstrated superior efficacy compared to bupropion monotherapy alone 2
• Long-term studies: Remission rates approached 70% and response rates exceeded 80% with sustained treatment over 12-15 months 2

Real-World Usage Patterns

In clinical practice since approval, Auvelity has been utilized across diverse treatment scenarios:

• 28.8% of patients initiated Auvelity as monotherapy 3
• 71.2% used it as add-on therapy, most commonly with SSRIs (10.7%) or SNRIs (6.5%) 3
• 10.1% were treatment-naïve patients starting Auvelity as first-line therapy 3
• 83.7% had previously tried SSRIs, bupropion (NDRI), or SNRIs before initiating Auvelity 3

Safety and Tolerability

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

Important Safety Considerations:

• Seizure risk: Bupropion lowers the seizure threshold; avoid in patients with epilepsy or seizure history 4
• Contraindications: Do not use with monoamine oxidase inhibitors or within 14 days of discontinuation 5
• Drug interactions: Bupropion's CYP2D6 inhibition may affect metabolism of other medications 4
• Abuse potential: While bupropion shows some CNS stimulant properties in animal studies, the recommended divided dosing is unlikely to be significantly reinforcing 4

Clinical Positioning

Auvelity represents a mechanistically novel option that can be used as first-line therapy, after failure of serotonin-targeting agents, or in treatment-resistant depression. 6

The combination offers several advantages over traditional second-generation antidepressants:

• Faster onset: Therapeutic effects within 2 weeks versus the typical 4-6 week lag with monoamine-targeting agents 2, 7
• Novel mechanism: NMDA receptor antagonism provides an alternative pathway for patients who have not responded to SSRIs, SNRIs, or other traditional antidepressants 6, 7
• Familiar components: Both dextromethorphan and bupropion are well-established medications, increasing clinician acceptability 6

Comparison to Traditional Antidepressants:

While the American College of Physicians guidelines recommend selecting between cognitive behavioral therapy or second-generation antidepressants for MDD 5, Auvelity's approval post-dates these 2016 guidelines and offers a distinct pharmacologic approach through glutamate modulation rather than monoamine reuptake inhibition.