dextromethorphan bupropion

General Information

Dextromethorphan-bupropion (Auvelity) is an oral combination antidepressant indicated for major depressive disorder (MDD) in adults (label).

It combines dextromethorphan (an NMDA receptor antagonist and sigma-1 receptor agonist) with bupropion, which inhibits CYP2D6 to increase dextromethorphan exposure; this CYP effect is built into the medication’s design (label).

Because bupropion is part of the regimen, seizure risk and blood pressure effects are central safety topics; screening for contraindications and risk factors is typical before initiation (label/clinical).

As with other antidepressants, monitoring for suicidal thoughts and behaviors is emphasized during initiation and dose changes (label).

The dextromethorphan-bupropion compare view, evidence feed, and print page support medication selection in complex regimens.

Auvelity is a convenient oral option with a novel mechanism compared with standard monoamine reuptake inhibitors, but interaction management and bupropion-related contraindications (seizure risk, eating disorders) are common limiting factors in practice (label/clinical).

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Dextromethorphan provides uncompetitive NMDA receptor antagonism and sigma-1 receptor agonism, while bupropion contributes norepinephrine/dopamine reuptake inhibition and CYP2D6 inhibition that increases dextromethorphan exposure (label/clinical).

The combination is often framed as targeting glutamatergic signaling and neuroplasticity pathways alongside monoaminergic effects, but clinical response still varies and requires follow-up like other antidepressants (clinical).

• NMDA receptor antagonism (dextromethorphan component).
• Sigma-1 receptor agonism (dextromethorphan component).
• Norepinephrine/dopamine reuptake inhibition and CYP2D6 inhibition (bupropion component).

Metabolism and Pharmacokinetics

• Dextromethorphan is primarily metabolized by CYP2D6 to dextrorphan. Bupropion is extensively metabolized, with hydroxybupropion formation via CYP2B6 (label).
• Bupropion inhibits CYP2D6, increasing dextromethorphan exposure and prolonging mean elimination half-life to ~22 hours at steady state; mean bupropion half-life is ~15 hours (label).
• Because CYP2D6 status and strong CYP2D6 inhibitors meaningfully affect dextromethorphan exposure, dose adjustment to once-daily dosing is recommended in those settings (label).

Dosing and Administration

• Recommended starting regimen: one tablet once daily in the morning; after 3 days, increase to one tablet twice daily given at least 8 hours apart (label).
• The label states not to exceed two doses within the same day (label).
• Moderate renal impairment: one tablet once daily in the morning (label).
• Strong CYP2D6 inhibitors or known CYP2D6 poor metabolizers: one tablet once daily in the morning (label).
• In clinical practice, early follow-up often focuses on dizziness/somnolence, sleep effects, and blood pressure, especially when other activating agents are present (clinical).

Monitoring & Labs

• Suicidal thoughts and behaviors monitoring during initiation and dose changes (label).
• Blood pressure and heart rate monitoring, especially with concomitant stimulants or noradrenergic agents (label/clinical).
• Seizure risk screening (history, eating disorder risk, abrupt sedative/alcohol withdrawal) (label/clinical).
• Serotonin syndrome monitoring when combined with serotonergic agents (label/clinical).
• Mania/hypomania monitoring in bipolar-spectrum illness (clinical).

Adverse Effects

Interactions

• MAOIs are contraindicated (and require washout) due to risk of serious and potentially fatal drug interactions, including hypertensive crisis and serotonin syndrome (label).
• Strong CYP2D6 inhibitors increase dextromethorphan concentrations; once-daily dosing is recommended and monitoring for dizziness/somnolence is typical (label).
• Strong CYP2B6 inducers (e.g., carbamazepine) can reduce exposure to both components and may reduce efficacy; avoidance is commonly recommended (label).
• Bupropion and its metabolites inhibit CYP2D6 and can raise exposure to CYP2D6 substrates (including some antidepressants, antipsychotics, and beta-blockers); interaction review is often safety-critical in polypharmacy (label/clinical).
• Co-administration with other agents that lower seizure threshold can increase seizure risk (label/clinical).

Other Useful Information

• Because the regimen is scheduled (not PRN), adherence routines and early tolerability check-ins are commonly emphasized, especially during the initial once-daily to twice-daily transition (clinical).
• In treatment-resistant or complex depression, clinicians often document symptom targets and a time-bounded reassessment plan after an adequate trial (APA/clinical).

References