What is the recommended treatment regimen for Auvelity (dextromethorphan-bupropion) in adults with major depressive disorder?

Auvelity Dosing Regimen for Major Depressive Disorder

Start Auvelity at 1 tablet (dextromethorphan 45 mg/bupropion 105 mg) once daily in the morning, then escalate weekly: Week 2 advance to 1 tablet twice daily, Week 3 advance to 2 tablets morning plus 1 tablet afternoon, and Week 4 reach the maintenance dose of 2 tablets twice daily. 1

Titration Schedule

The FDA-approved titration follows a structured 4-week escalation:

• Week 1: 1 tablet once daily (morning)
• Week 2: 1 tablet twice daily (morning and afternoon)
• Week 3: 2 tablets in morning + 1 tablet in afternoon
• Week 4 onward: 2 tablets twice daily (maintenance dose) 1

Take the second daily dose earlier in the day, not late afternoon or evening, to minimize insomnia risk. 1

Dose Adjustments for Organ Impairment

Renal Impairment

• Moderate to severe renal impairment: Reduce total daily dose by half (maximum 1 tablet twice daily) 1
• End-stage renal disease: Avoid Auvelity entirely 1

Hepatic Impairment

• Moderate to severe hepatic impairment: Do not exceed 1 tablet daily total 1

Treatment Response Assessment

Discontinue Auvelity after 12 weeks at maintenance dose if the patient has not lost 5% of baseline body weight—this guidance comes from obesity literature but reflects the principle of identifying poor responders. 1 For depression specifically, clinical trials demonstrated significant Montgomery-Åsberg Depression Rating Scale (MADRS) reductions within 2 weeks, with remission rates approaching 70% and response rates exceeding 80% in long-term studies. 2

Clinical Context and Positioning

Auvelity represents a mechanistically novel approach combining NMDA receptor antagonism (dextromethorphan) with increased dextromethorphan bioavailability via CYP2D6 inhibition (bupropion). 2, 3 Real-world data shows 28.8% of patients initiate Auvelity as monotherapy, while 71.2% use it as add-on therapy, most commonly with SSRIs (10.7%) or SNRIs (6.5%). 4 Notably, 10.1% of patients were treatment-naïve when starting Auvelity. 4

The combination can be positioned as:

• First-line therapy for treatment-naïve patients 3
• Second-line option after SSRI/SNRI failure 3
• Treatment for resistant depression 3

Critical Safety Considerations

Absolute Contraindications

• Monoamine oxidase inhibitors: Avoid Auvelity if patient is taking MAOIs or within 14 days of MAOI discontinuation 1
• Opioid therapy: Do not use in patients requiring short-term or long-term opiates, as the naltrexone component (from obesity formulation context) could precipitate withdrawal or reduce analgesic efficacy—though this specifically applies to naltrexone-bupropion, not dextromethorphan-bupropion 1
• Uncontrolled hypertension: Avoid use 1

Seizure Risk

Bupropion lowers seizure threshold—avoid in patients with epilepsy and use extreme caution in those with seizure history or risk factors. 1 This risk increases at higher doses. 5

Suicidality Monitoring

All antidepressants, including Auvelity, carry a boxed warning for increased suicidal thoughts and behaviors, particularly in patients under age 24. 5 Monitor closely, especially during initial weeks and dose changes.

Common Adverse Effects

The most frequent side effects (generally mild-to-moderate) include: 2, 5

• Dizziness
• Nausea
• Headache
• Diarrhea
• Somnolence
• Dry mouth
• Sexual dysfunction
• Hyperhidrosis (excessive sweating)
• Anxiety
• Constipation
• Decreased appetite
• Insomnia

Monitoring Parameters

• Vital signs: Monitor blood pressure regularly, as bupropion can elevate blood pressure 1
• Depression severity: Use PHQ-9 or HAM-D scales to quantify response (≥50% reduction indicates response) 6
• Suicidality assessment: Particularly in first 2-4 weeks and after dose increases 5
• Seizure precautions: Counsel patients on seizure warning signs 5

Advantages Over Traditional Antidepressants

Auvelity demonstrates rapid onset of antidepressant effects within 2 weeks, compared to the typical 6-12 week timeline for SSRIs. 2 This represents a significant clinical advantage for patients requiring faster symptom relief. Long-term open-label studies maintained these improvements through 12-15 months of treatment. 2

The combination provides pharmacokinetic synergy (bupropion increases dextromethorphan levels) and pharmacodynamic synergy (complementary mechanisms of action), which may explain the rapid efficacy. 7

Common Pitfalls to Avoid

• Rushing titration: Follow the weekly escalation schedule to optimize tolerability 1
• Late-day dosing: Avoid taking second dose late in day due to insomnia risk 1
• Ignoring organ function: Always adjust for renal/hepatic impairment 1
• Premature discontinuation: Allow adequate trial duration (at least 12 weeks at maintenance dose) before declaring treatment failure 1
• Missing drug interactions: Screen for MAOIs, opioids, and other CYP2D6 substrates 1
• Inadequate suicidality monitoring: Intensify monitoring in young adults and early treatment phases 5