What are the dosing regimen, contraindications, precautions, adverse effects, and monitoring recommendations for Auvelity (dextromethorphan/bupropion) in adult patients with major depressive disorder?

Auvelity (Dextromethorphan/Bupropion) for Major Depressive Disorder

Dosing Regimen

Auvelity is dosed as a fixed-dose combination of dextromethorphan hydrobromide 45 mg and bupropion hydrochloride 105 mg, with the bupropion component serving primarily to inhibit CYP2D6 and increase dextromethorphan bioavailability rather than as an independent antidepressant dose. 1, 2

• The medication is administered orally as a fixed-dose combination tablet 2
• Bupropion's role in this formulation is specifically to inhibit CYP2D6 metabolism, thereby increasing dextromethorphan bioavailability rather than providing therapeutic antidepressant effects at this dose 1, 2

Clinical Indications and Patient Selection

Auvelity is FDA-approved for treatment of major depressive disorder in adults and can be used as first-line therapy, after failure of serotonin-targeting agents, or in treatment-resistant depression. 3, 2

• Consider Auvelity as first-line monotherapy in treatment-naïve patients with MDD, as 10.1% of real-world patients initiated it without prior treatment 4
• Use as second-line therapy after inadequate response to SSRIs or SNRIs, which is the most common real-world pattern 4
• Consider for treatment-resistant depression, though evidence is mixed in this population 5
• In real-world practice, 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
• When selecting Auvelity, discuss treatment effects, expected timeline, adverse effect profile, cost, insurance coverage, and patient preferences regarding prior medication experiences 6

Contraindications and Precautions

Auvelity contains bupropion, which carries established contraindications including seizure disorders, eating disorders, and concurrent use with monoamine oxidase inhibitors. 7

• Avoid in patients with seizure history or conditions that lower seizure threshold 7
• Contraindicated in patients with current or prior eating disorders (bulimia or anorexia nervosa) 7
• Do not use concurrently with MAO inhibitors due to bupropion component 7
• Exercise caution in patients with hepatotoxicity risk, as this is a monitored adverse effect with second-generation antidepressants 7

Adverse Effects Profile

The most common adverse events with Auvelity are mild-to-moderate in severity, with dizziness, nausea, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and anxiety being most frequently reported. 1

• Auvelity demonstrates a favorable sexual adverse event profile compared to SSRIs, as the bupropion component is associated with significantly lower rates of sexual dysfunction than fluoxetine or sertraline 7, 8
• Common adverse events include constipation, diarrhea, dizziness, headache, insomnia, nausea, and somnolence 7
• Monitor for suicidality, particularly during the first 1-2 months of treatment, as SSRIs show increased risk for suicide attempts compared to placebo, though this specific risk profile for Auvelity requires vigilance 7
• Long-term studies demonstrate sustained tolerability through 12-15 months of treatment 1
• Discontinuation rates due to adverse events are generally low, with most adverse effects rated as mild-to-moderate 1

Monitoring Recommendations

Begin monitoring therapeutic response and adverse effects within 1-2 weeks of initiating Auvelity, and evaluate for treatment modification if adequate response is not achieved within 6-8 weeks. 7, 6, 8

• Initiate close monitoring within 1-2 weeks of therapy initiation for emergence of suicidal thoughts, agitation, irritability, or unusual behavioral changes 7, 6
• The risk for suicide attempts is greatest during the first 1-2 months of treatment 7
• Assess therapeutic response at 6-8 weeks; if inadequate, consider treatment modification including augmentation or switching strategies 7, 6
• Monitor for specific adverse events including hyponatremia, seizures, hepatotoxicity, weight changes, gastrointestinal symptoms, and sexual adverse events 7
• Auvelity demonstrates rapid onset with significant reductions in Montgomery-Åsberg Depression Rating Scale scores within 2 weeks, earlier than traditional antidepressants 1

Treatment Duration

Continue Auvelity for 4-9 months after achieving satisfactory response in patients with first-episode major depressive disorder; patients with two or more prior depressive episodes require longer duration therapy. 6, 8

• For first-episode MDD with satisfactory response, treat for 4-9 months 6
• For patients with 2 or more prior depressive episodes, continue treatment beyond 9 months 6, 8
• Long-term open-label studies demonstrate maintained efficacy through 12-15 months with remission rates approaching 70% and response rates exceeding 80% 1

Efficacy and Expected Outcomes

Auvelity demonstrates rapid antidepressant effects within 2 weeks and achieves significantly higher remission and response rates compared to placebo and bupropion monotherapy. 1

• Phase 3 trials show significant reductions in Montgomery-Åsberg Depression Rating Scale total scores compared to placebo 1
• Phase 2 trials demonstrate superiority over bupropion monotherapy alone 1
• Therapeutic changes are evident within 2 weeks, substantially faster than the typical 4-6 week lag with traditional monoamine-targeting antidepressants 1, 5
• Long-term studies show remission rates approaching 70% and response rates greater than 80% 1

Common Clinical Pitfalls

• Do not assume the bupropion dose in Auvelity (105 mg) provides full antidepressant effects—it primarily serves to inhibit CYP2D6 metabolism 1, 2
• Avoid premature discontinuation before the 6-8 week evaluation point, though Auvelity shows earlier effects than traditional antidepressants 7, 6
• Do not overlook seizure risk assessment before initiation, as bupropion lowers seizure threshold 7
• Remember that while Auvelity can be used as monotherapy, 71.2% of real-world patients use it as add-on therapy, most commonly with SSRIs or SNRIs 4