Auvelity
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NMDA receptor antagonist + sigma-1 agonist + NDRI (combination)
Auvelity
Auvelity (dextromethorphan/bupropion ER)
Auvelity is a fixed-dose combination of dextromethorphan 45 mg and bupropion 105 mg, FDA-approved August 2022 for major depressive disorder. The combination addresses dextromethorphan's rapid first-pass CYP2D6 metabolism by exploiting bupropion's CYP2D6 inhibition, without bupropion, oral dextromethorphan never reaches plasma levels sufficient for NMDA antagonism. The rationale builds on ketamine's antidepressant effect: low-dose NMDA antagonism may produce rapid antidepressant response through downstream AMPA/BDNF/synaptogenesis pathways rather than monoamine modulation. Significant antidepressant separation from placebo by week 1 in trials.
Dextromethorphan: Uncompetitive NMDA receptor antagonist (binds open channel like ketamine/memantine), sigma-1 receptor agonist, modest SERT and NET inhibition. Bupropion: Norepinephrine-dopamine reuptake inhibitor (NDRI) plus potent CYP2D6 inhibition (blocking dextromethorphan's metabolism to dextrorphan).
Experience
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Effects
Dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction. Lower seizure risk than higher-dose bupropion alone. Avoid in patients with seizure disorders or eating disorders (bupropion contraindication). Avoid with MAOIs (serotonin syndrome / hypertensive crisis risk).
Pharmacodynamics
Interactions
Fluoxetine via Category:Antidepressants exp n/a/5 outcome n/a (n=1) exp 1.0/5 outcome +33.0 (n=1)
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Summary
Classes
NMDA receptor antagonist + sigma-1 agonist + NDRI (combination)
Common uses
Major depressive disorder in adults (FDA-approved August 2022)
Pharmacy
Starting dose
1 tablet (dextromethorphan 45 mg / bupropion 105 mg) PO daily × 3 days, then increase to 1 tablet BID
Preparations
Dextromethorphan 45 mg + bupropion 105 mg ER tablets
US FDA Max
2 tablets/day (dextromethorphan 90 mg / bupropion 210 mg)
Pharmacology
Routes
Oral
Onset
Significant antidepressant response by week 1 in trials (faster than monoaminergic antidepressants which take 4-6 weeks)
Duration
Sustained with twice-daily dosing
Half-life
Dextromethorphan ~22 h (when CYP2D6 inhibited); bupropion ~21 h
Bioavailability
Not formally characterized for the combination
Pregnancy
Limited data; avoid
Legal status
Rx
Purported mechanism
Fixed-dose combination of dextromethorphan 45 mg (NMDA antagonist + sigma-1 agonist + SERT/NET inhibition) with bupropion 105 mg (NDRI). Bupropion's role is dual: provides NDRI antidepressant action AND inhibits CYP2D6 to slow dextromethorphan metabolism, achieving therapeutic plasma levels that are otherwise unattainable due to rapid first-pass metabolism.