Is Auvelity (dextromethorphan/bupropion) suitable as second‑line therapy for an adult with major depressive disorder who failed an adequate trial of a selective serotonin reuptake inhibitor (SSRI) or serotonin‑norepinephrine reuptake inhibitor (SNRI), and what are the dosing and safety considerations?

Auvelity as Second-Line Therapy for Major Depressive Disorder

Direct Recommendation

Auvelity (dextromethorphan/bupropion) is an appropriate second-line option for adults with MDD who have failed an adequate SSRI or SNRI trial, offering rapid onset of antidepressant effects (within 1 week) and a novel glutamatergic mechanism that differs from traditional monoamine-based therapies. 1, 2, 3

Evidence Supporting Second-Line Use

Positioning in Treatment Algorithm

• Real-world data demonstrates that 83.7% of patients initiating Auvelity had previously received SSRIs, SNRIs, or bupropion monotherapy, confirming its established role as a second-line agent. 4

• The American College of Physicians guideline framework supports modifying treatment at 6-8 weeks if inadequate response occurs with first-line SSRI/SNRI therapy, with evidence showing similar efficacy across different second-step strategies (switching vs. augmentation). 5, 6

• Auvelity can be initiated either as monotherapy (28.8% of real-world patients) or as add-on therapy (71.2% of patients), most commonly added to an existing SSRI (10.7%) or SNRI (6.5%). 4

Efficacy Profile

• Phase 2 and Phase 3 trials demonstrated significant reductions in MADRS and CGI-S scores compared to placebo, with clinically meaningful improvement observed as early as week 1 of treatment—substantially faster than the typical 4-6 week lag with traditional antidepressants. 2, 3, 7

• The combination provides pharmacokinetic synergy: bupropion inhibits CYP2D6, increasing dextromethorphan plasma levels and enhancing its NMDA receptor antagonism and sigma-1 receptor agonism. 2, 3

• Dextromethorphan/bupropion represents a mechanistically novel approach targeting glutamatergic signaling rather than solely monoamine systems, potentially beneficial for patients who have not responded to serotonin-targeting agents. 1, 2

Dosing Considerations

Standard Dosing Protocol

• Initiate Auvelity at 45 mg dextromethorphan/105 mg bupropion, which is the studied and approved dose demonstrated effective in clinical trials. 3

• The medication combines a noncompetitive NMDA receptor antagonist (dextromethorphan) with a CYP2D6 inhibitor (bupropion) in a fixed-dose combination. 3

Monitoring Timeline

• Assess therapeutic response at 1 week, as clinical improvement can be observed this early—unlike traditional antidepressants requiring 4-6 weeks. 2, 3

• Continue monitoring at 1-2 week intervals initially for adverse effects and suicidality, consistent with standard antidepressant monitoring protocols. 6

• If inadequate response persists at 6-8 weeks, consider alternative second-step strategies per American College of Physicians recommendations. 6, 8

Safety Considerations

Adverse Event Profile

• Auvelity demonstrated similar adverse effects to bupropion monotherapy in clinical trials, with the combination being well-tolerated across studies. 2, 3, 7

• Real-world data from 22,288 patients showed acceptable tolerability, with the medication being prescribed across diverse demographic groups (mean age 45.1 years, 68.1% women). 4

Critical Safety Monitoring

• Monitor intensively for agitation, irritability, or unusual behavioral changes during the first 1-2 months, as these may indicate worsening depression rather than treatment response. 6

• Assess for suicidal ideation and behavior at 1-2 week intervals initially, particularly given the rapid onset of action. 6

• Be aware of bupropion's CYP3A4 induction potential, which may affect oral contraceptives and immunosuppressants requiring dose adjustments. 6

• Contraindications include seizure disorders (due to bupropion), concurrent MAOI use, and conditions where bupropion is contraindicated. 3

Drug Interaction Considerations

• The dextromethorphan component is metabolized via CYP2D6, and bupropion competitively inhibits this pathway—this interaction is intentional and therapeutic. 3

• Exercise caution with other serotonergic agents due to theoretical serotonin syndrome risk, though clinical data suggests this combination can be used safely with monitoring. 9

Comparison to Alternative Second-Line Strategies

Relative to Other Augmentation Options

• The American College of Physicians found that augmenting SSRIs with bupropion decreased depression severity more than buspirone, with lower discontinuation rates due to adverse events (12.5% vs. 20.6%). 6, 8

• Bupropion augmentation specifically offers the advantage of lower sexual dysfunction rates compared to SSRI/SNRI monotherapy. 6

• Aripiprazole augmentation showed higher remission rates (55.4%) compared to bupropion augmentation (34.0%) in one trial, though aripiprazole carries metabolic and extrapyramidal side effect risks. 8

Relative to Switching Strategies

• Moderate-quality evidence shows no significant differences in efficacy when switching from one second-generation antidepressant to another (bupropion SR, escitalopram, duloxetine, sertraline, or venlafaxine). 5, 8

• The American College of Physicians emphasizes that the choice between switching versus augmenting is less important than trying a different evidence-based approach. 8

Relative to Non-Pharmacologic Options

• Adding cognitive behavioral therapy has similar efficacy to medication augmentation with potentially fewer adverse events (9.2% vs. 18.8% discontinuation rates). 6, 8

Clinical Scenarios for Auvelity Use

As Monotherapy After SSRI/SNRI Failure

• Auvelity can be initiated as monotherapy after discontinuing the failed SSRI/SNRI, representing a complete switch to a mechanistically different agent. 1, 4

• This approach is appropriate when the patient experienced intolerable side effects or complete lack of response to the initial agent. 1

As Add-On Therapy

• Auvelity can be added to an existing SSRI or SNRI for patients with partial response, leveraging the complementary mechanisms of serotonergic and glutamatergic modulation. 1, 4

• Real-world data shows this is the most common approach (71.2% of patients), particularly adding to SSRIs or SNRIs. 4

For Treatment-Resistant Depression

• The combination can be considered for treatment-resistant depression, though evidence is mixed and additional studies are needed in this specific population. 7

Duration of Treatment

• Continue treatment for 4-9 months after achieving satisfactory response in patients with a first episode of MDD. 6

• Consider years to lifelong maintenance therapy for patients with two or more prior depressive episodes. 6

• Maintain the same dosage that achieved remission during the continuation phase to prevent relapse. 6

Common Pitfalls to Avoid

• Do not wait indefinitely for monotherapy response—modify treatment at 6-8 weeks if inadequate improvement occurs. 6, 8

• Do not overlook the rapid onset advantage when counseling patients—set appropriate expectations for improvement within 1 week rather than 4-6 weeks. 2, 3

• Do not assume all augmentation strategies are equivalent—bupropion specifically outperforms buspirone for depression severity reduction. 6

• Do not discontinue abruptly—follow standard antidepressant tapering protocols to avoid discontinuation syndrome. 9

• Do not overlook the sexual dysfunction advantage of bupropion-containing regimens when discussing treatment options with patients. 6