When should Auvelity (dextromethorphan/bupropion) be prescribed to adult patients with major depressive disorder?

When to Prescribe Auvelity for Major Depressive Disorder

Auvelity (dextromethorphan/bupropion) should be prescribed to adults with major depressive disorder either as first-line monotherapy, as second-line treatment after inadequate response to SSRIs/SNRIs within 6-8 weeks, or as add-on therapy to existing antidepressants when patients have not achieved remission. 1, 2

Clinical Scenarios for Auvelity Initiation

First-Line Monotherapy

• Auvelity can be initiated as first-line treatment for adults with MDD, particularly when rapid onset of action is desired, as clinical trials demonstrated significant symptom reduction within 2 weeks compared to placebo. 1
• Real-world data shows that 10.1% of patients initiated Auvelity without any prior MDD treatment in the preceding 12 months, and 28.8% used it as monotherapy rather than add-on therapy. 2
• The American College of Physicians recommends discussing treatment effects, adverse effect profiles, cost, and accessibility with patients when selecting between pharmacotherapy options for MDD. 3

Second-Line Treatment After SSRI/SNRI Failure

• Prescribe Auvelity when patients fail to achieve adequate response after 6-8 weeks of initial antidepressant therapy with SSRIs or SNRIs. 4
• In real-world practice, 83.7% of patients who received Auvelity had previously tried SSRIs (54.9%), bupropion alone (40.4%), or SNRIs (35.9%) in the 12 months before starting Auvelity. 2
• The American College of Physicians emphasizes that modifying treatment at 6-8 weeks is appropriate when response is inadequate, and the choice of second-step strategy matters less than trying a different evidence-based approach. 4

Add-On/Augmentation Therapy

• Auvelity is most commonly prescribed as add-on therapy (71.2% of real-world users), particularly added to SSRIs (10.7% of cases) or SNRIs (6.5% of cases). 2
• This augmentation approach aligns with American College of Physicians guidance that augmenting with another medication is a reasonable strategy when initial antidepressant monotherapy fails. 4
• The combination targets different neurotransmitter systems—dextromethorphan modulates glutamate signaling through NMDA receptor antagonism and sigma-1 agonism, while bupropion increases norepinephrine and dopamine. 1

Patient Selection Criteria

Appropriate Candidates

• Adults with diagnosed MDD (ICD-10 codes F32., F33.) who require antidepressant treatment. 2
• Patients with comorbid anxiety disorders (47.6% of real-world Auvelity users had anxiety), as the medication has been used successfully in this population. 2
• Patients who need faster onset of action, as Auvelity demonstrated significant MADRS score reductions within 2 weeks in phase 2 and 3 trials. 1
• Patients with treatment-resistant depression who have failed multiple prior antidepressant trials. 5

Patients Requiring Caution

• Pediatric and young adult patients require careful monitoring due to the boxed warning for increased risk of suicidal thoughts and behaviors with all antidepressants. 6
• Patients with seizure history or risk factors, as seizures can occur and are more likely at higher doses. 6
• Patients taking other serotonergic medications require monitoring for serotonin syndrome risk. 7

Timing and Monitoring

Initial Assessment

• Begin monitoring therapeutic response and adverse effects within 1-2 weeks of starting treatment. 4
• Evaluate for suicidal ideation increases during the first 1-2 months, particularly in younger patients. 4

Treatment Modification Timeline

• Assess response at 6-8 weeks; if inadequate, consider dose adjustment or switching strategies. 4
• Continue treatment for 4-9 months after achieving satisfactory response during the continuation phase. 4
• Consider longer duration (≥1 year maintenance phase) for patients with 2 or more prior depressive episodes. 4

Long-Term Outcomes

• Open-label studies showed large MADRS score reductions maintained through 12-15 months of treatment, with remission rates approaching 70% and response rates exceeding 80%. 1

Common Adverse Effects to Discuss

• The most common adverse effects include dizziness, nausea, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, hyperhidrosis, anxiety, constipation, decreased appetite, and insomnia—most rated as mild-to-moderate in clinical trials. 6, 1
• These side effects should be weighed against the medication's rapid onset of action and high remission rates when counseling patients. 1

Comparison to Standard Treatment Algorithms

• The American College of Physicians recommends selecting between cognitive behavioral therapy or second-generation antidepressants as first-line treatment, with no specific preference for one antidepressant over another based on moderate-quality evidence. 3
• Auvelity represents a novel mechanism (NMDA antagonism plus dopamine/norepinephrine reuptake inhibition) distinct from traditional SSRIs/SNRIs, making it a reasonable alternative when standard approaches fail. 1, 5
• Real-world adoption within one year of FDA approval (22,288 patients) demonstrates clinical acceptance across diverse practice settings. 2