Can I start Auvelity (dextromethorphan/bupropion) in an adult with major depressive disorder, and what are the recommended dosing, contraindications, monitoring parameters, and alternative treatments?

Auvelity for Major Depressive Disorder

Auvelity (dextromethorphan/bupropion) is an FDA-approved treatment option for adults with major depressive disorder that can be initiated as first-line therapy, after failed SSRI/SNRI trials, or as add-on treatment, with demonstrated rapid onset of antidepressant effects. 1, 2

Dosing Schedule

Titration Protocol:

• Week 1: 1 tablet (45 mg dextromethorphan/105 mg bupropion) once daily in the morning 1
• Week 2 onward: 1 tablet twice daily (morning and evening), at least 8 hours apart 1
• Maximum dose: 2 tablets daily 1

The extended-release formulation should be swallowed whole and not crushed, chewed, or divided 1.

Absolute Contraindications

Do not prescribe Auvelity if the patient has: 3, 4

• Current or recent (within 14 days) monoamine oxidase inhibitor (MAOI) use
• Seizure disorder or history of seizures (bupropion lowers seizure threshold)
• Bulimia nervosa or anorexia nervosa (current or past)
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs
• Current use of other bupropion-containing products
• Hypersensitivity to dextromethorphan or bupropion

Critical Monitoring Parameters

Initial Assessment (Before Starting):

• Screen for personal or family history of bipolar disorder, mania, or hypomania 3
• Document seizure history and risk factors (head trauma, CNS tumor, eating disorders) 3
• Assess for concurrent medications metabolized by CYP2D6 1
• Evaluate for active substance use disorders 3

Ongoing Monitoring:

• Week 1-2: Assess for suicidal ideation, worsening depression, or unusual behavioral changes (highest risk period for young adults) 3
• Weeks 6-8: Evaluate treatment response; if inadequate improvement, consider treatment modification 5
• Monitor blood pressure periodically (bupropion can increase BP) 3
• Assess for angle-closure glaucoma symptoms (eye pain, vision changes) 3

Common Adverse Effects

Most Frequent (counsel patients to expect): 3

• Dizziness, nausea, headache (typically transient)
• Diarrhea, dry mouth, constipation
• Somnolence or insomnia
• Sexual dysfunction
• Hyperhidrosis, decreased appetite
• Anxiety (paradoxical in some patients)

Serious Risks Requiring Patient Education: 3

• Seizure risk increases at higher doses
• Suicidal thoughts/behaviors (particularly in patients <25 years old)
• Activation of mania/hypomania in undiagnosed bipolar disorder
• Angle-closure glaucoma

Treatment Duration

Continue therapy for 4-9 months after achieving satisfactory response in first-episode MDD; patients with two or more prior depressive episodes require longer maintenance treatment. 5 This aligns with standard continuation phase treatment to prevent relapse 4.

Clinical Positioning

Auvelity can be used in three scenarios: 2, 6

1. First-line monotherapy: Appropriate initial choice, particularly when sexual dysfunction concerns exist (bupropion has lower sexual side effects than SSRIs) 4

2. Second-line after SSRI/SNRI failure: Real-world data shows 83.7% of patients had prior SSRI, SNRI, or bupropion trials 6

3. Add-on therapy: 71.2% of patients in real-world practice initiated Auvelity as augmentation, most commonly added to SSRIs (10.7%) or SNRIs (6.5%) 6

Alternative Treatment Considerations

The American College of Physicians recommends discussing both cognitive behavioral therapy (CBT) and second-generation antidepressants with patients before selecting treatment. 4 CBT shows similar efficacy to pharmacotherapy with potentially fewer adverse effects and lower relapse rates 4. However, CBT accessibility and patient preference are practical considerations 4.

Other pharmacologic alternatives include: 4

• SSRIs (citalopram, escitalopram, fluoxetine, sertraline, paroxetine)
• SNRIs (venlafaxine, duloxetine, desvenlafaxine)
• Other SGAs (mirtazapine, vortioxetine, vilazodone)

Bupropion monotherapy (without dextromethorphan) remains an option with established lower sexual dysfunction rates compared to SSRIs 4.

Key Clinical Pitfalls

Avoid these common errors:

• Missing undiagnosed bipolar disorder (can precipitate manic episode) 3
• Combining with MAOIs or failing to observe 14-day washout period 4
• Prescribing to patients with eating disorders or seizure history 3
• Abrupt discontinuation at higher doses (taper over at least 1 week) 4
• Overlooking drug interactions via CYP2D6 inhibition 4, 1
• Failing to counsel young adults about increased suicidality risk 3

Mechanism and Rapid Onset

Auvelity combines dextromethorphan (NMDA receptor antagonist and sigma-1 receptor agonist) with bupropion (which inhibits CYP2D6 to increase dextromethorphan bioavailability and provides norepinephrine-dopamine reuptake inhibition) 1, 7. This pharmacokinetic and pharmacodynamic synergy produces relatively rapid antidepressant effects compared to traditional monoamine-based antidepressants 7.