Auvelity (Dextromethorphan/Bupropion) for Major Depressive Disorder

Direct Answer

Auvelity is dosed at 45 mg dextromethorphan/105 mg bupropion twice daily (morning and before 3 PM), offers rapid antidepressant effects within 1–2 weeks, and can be used as first-line therapy, after SSRI failure, or in treatment-resistant depression. 1, 2

Dosing and Administration

Standard Dosing Protocol

Start Auvelity at 45 mg dextromethorphan/105 mg bupropion twice daily from day 1—no titration is required. 1, 2
Administer the first dose in the morning and the second dose before 3 PM to minimize insomnia risk, following the same timing principles as bupropion SR. 3
The maximum daily dose is 90 mg dextromethorphan/210 mg bupropion (two tablets daily). 1

Dose Adjustments for Special Populations

For moderate to severe hepatic impairment, reduce the total daily dose to one tablet (45/105 mg) once daily, as bupropion accumulation occurs with liver dysfunction. 3
For moderate to severe renal impairment (eGFR < 90 mL/min), reduce the dose by 50% (one tablet daily instead of two), because both dextromethorphan and bupropion metabolites are renally cleared. 3
Avoid Auvelity entirely in end-stage renal disease, as metabolite accumulation cannot be adequately managed even with dose reduction. 3
For older adults (≥ 65 years), no specific dose adjustment is mandated, but start with close monitoring given the bupropion component's activating properties. 3

Mechanism and Pharmacology

Synergistic Combination

Dextromethorphan acts as an uncompetitive NMDA receptor antagonist and sigma-1 receptor agonist, modulating glutamatergic signaling—a novel mechanism distinct from monoamine-based antidepressants. 4, 1, 2
Bupropion inhibits CYP2D6, increasing dextromethorphan bioavailability approximately 20-fold, while also contributing norepinephrine-dopamine reuptake inhibition. 4, 1, 2
This pharmacokinetic and pharmacodynamic synergy accounts for the rapid onset of antidepressant effects within 1–2 weeks, significantly faster than traditional SSRIs. 4, 1

Clinical Efficacy

Pivotal Trial Data

In phase 3 trials, Auvelity produced significant reductions in Montgomery-Åsberg Depression Rating Scale (MADRS) scores compared to placebo within 2 weeks, with sustained benefit through 6 weeks. 1
A phase 2 trial comparing Auvelity to bupropion monotherapy showed significantly greater MADRS score reduction with the combination, demonstrating that dextromethorphan adds meaningful efficacy beyond bupropion alone. 1
Remission rates approached 70% and response rates exceeded 80% in long-term open-label studies extending 12–15 months, indicating durable efficacy. 1

Real-World Usage Patterns

In a 2024 analysis of 22,288 U.S. patients initiating Auvelity, 28.8% used it as monotherapy and 71.2% as add-on therapy, most commonly added to an SSRI (10.7%) or SNRI (6.5%). 5
Notably, 10.1% of patients were treatment-naïve, indicating acceptance as first-line therapy in clinical practice. 5
Most patients (83.7%) had previously tried SSRIs, SNRIs, or bupropion, confirming Auvelity's role after inadequate response to conventional antidepressants. 5

Indications and Treatment Positioning

When to Use Auvelity

First-line therapy for adults with moderate to severe MDD, particularly when rapid onset is desired or when patients have concerns about sexual dysfunction or weight gain associated with SSRIs. 6, 1
Second-line therapy after failure of an SSRI or SNRI monotherapy, offering a mechanistically distinct glutamatergic approach. 6, 5
Treatment-resistant depression (after ≥ 2 adequate antidepressant trials), as an alternative to ketamine/esketamine or atypical antipsychotic augmentation. 4, 6
Preliminary evidence supports use in bipolar depression, though this remains off-label and requires further study. 4

Advantages Over Other Antidepressants

Rapid onset (1–2 weeks vs. 6–8 weeks for SSRIs) addresses the critical early treatment window when suicide risk is highest. 1
Lower rates of sexual dysfunction compared to SSRIs, inherited from the bupropion component. 3
Minimal weight gain or potential weight loss, unlike SSRIs, SNRIs, and atypical antipsychotics. 3
Novel glutamatergic mechanism provides an option for patients who have exhausted monoamine-based therapies. 4, 1

Absolute Contraindications

Seizure-Related Contraindications

Any history of seizure disorder, epilepsy, or conditions predisposing to seizures (head trauma, brain tumor, stroke, brain metastases) is an absolute contraindication, as bupropion lowers the seizure threshold. 3
Eating disorders (bulimia nervosa or anorexia nervosa) carry increased seizure risk with bupropion and are contraindicated. 3
Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs is contraindicated due to markedly elevated seizure risk. 3

Drug Interaction Contraindications

Current or recent (within 14 days) use of monoamine oxidase inhibitors (MAOIs) is absolutely contraindicated. 3
Concurrent tamoxifen therapy is contraindicated, as bupropion inhibits CYP2D6 and reduces tamoxifen's conversion to its active metabolite. 3
Chronic opioid therapy is a relative contraindication if considering the naltrexone-bupropion combination, but does not apply to Auvelity (which contains dextromethorphan, not naltrexone). 3

Other Absolute Contraindications

Uncontrolled hypertension should preclude Auvelity use, as bupropion can elevate blood pressure and heart rate. 3
Closed-angle glaucoma is contraindicated due to risk of intraocular pressure elevation. 3

Common Adverse Effects

Most Frequent Side Effects

Dizziness, nausea, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis were the most common adverse events in clinical trials, typically rated as mild to moderate. 1
Insomnia can occur if the second dose is taken too late in the day; strict adherence to the before-3-PM timing minimizes this risk. 3
Agitation or behavioral activation may emerge, particularly in the first 1–2 weeks, requiring close monitoring. 3

Serious Adverse Effects

Seizure risk is approximately 0.1% (1 in 1,000) at the standard 210 mg/day bupropion dose contained in Auvelity, rising markedly if contraindications are ignored or doses are exceeded. 3
Hypertension and tachycardia can develop; baseline and periodic blood pressure monitoring (especially in the first 12 weeks) is mandatory. 3
Severe hypersensitivity reactions (urticaria, angioedema) occur in approximately 1 per 1,000 to 1 per 10,000 patients. 3

Black Box Warning

All antidepressants, including Auvelity, carry an FDA black-box warning for increased risk of suicidal thoughts and behaviors in patients younger than 24 years, with the greatest risk during the first 1–2 months of therapy. 3

Monitoring Requirements

Early Monitoring (Weeks 1–2)

Assess for suicidal ideation, agitation, irritability, or unusual behavioral changes within 1–2 weeks of initiation, as suicide-attempt risk peaks during the first 1–2 months of antidepressant treatment. 3, 7
Monitor for early adverse effects (nausea, dizziness, insomnia) and adherence to identify tolerability issues before they lead to discontinuation. 3

Ongoing Monitoring

Measure blood pressure and heart rate at baseline and periodically during treatment, especially in the first 12 weeks, to detect bupropion-induced elevations. 3
Assess therapeutic response using validated scales (PHQ-9, MADRS, HAM-D) at 2 weeks and again at 6–8 weeks to determine whether dose adjustment or treatment modification is needed. 7, 1
For patients with hepatic or renal impairment, monitor closely for adverse reactions due to drug and metabolite accumulation. 3

Response Assessment Timeline

Expect clinically meaningful improvement within 1–2 weeks, distinguishing Auvelity from SSRIs that require 6–8 weeks. 1
If inadequate response by 6–8 weeks, consider augmentation with CBT, switching to another agent, or adding adjunctive therapy rather than continuing ineffective treatment. 7

Treatment Duration

Acute and Continuation Phases

Continue Auvelity for at least 4–9 months after achieving satisfactory response in a first depressive episode to reduce relapse risk. 7
For recurrent depression (≥ 2 prior episodes), maintain therapy for ≥ 1 year or longer, as relapse risk rises to 70% after two episodes and 90% after three episodes. 7

Long-Term Safety

Open-label studies extending 12–15 months demonstrated sustained efficacy and acceptable tolerability, with remission rates approaching 70%. 1

Alternative Treatments for Major Depressive Disorder

First-Line Options (When Auvelity Is Not Chosen)

Cognitive-behavioral therapy (CBT) or a second-generation antidepressant (SSRI or SNRI) are strongly recommended as first-line treatments, with moderate-quality evidence showing equivalent efficacy. 7
SSRIs (sertraline, escitalopram, citalopram, fluoxetine, paroxetine) achieve remission with an NNT of 7–8 and are the most affordable option. 7
SNRIs (venlafaxine, duloxetine) may be slightly more effective than SSRIs for severe depression or comorbid chronic pain, though they carry higher rates of nausea. 7

Second-Line Options (After First-Line Failure)

Bupropion monotherapy (150 mg twice daily SR or 300 mg once daily XL) offers lower sexual dysfunction and weight gain compared to SSRIs. 3, 7
Mirtazapine (15–45 mg nightly) is effective for depression with insomnia or poor appetite, though sedation and weight gain are common. 7
Augmentation of an SSRI with bupropion or buspirone yields remission rates comparable to switching antidepressants, with bupropion showing better tolerability. 7

Treatment-Resistant Depression Options

Ketamine or esketamine produces rapid symptom reduction within 24 hours in patients who have failed ≥ 2 adequate antidepressant trials, supported by high-quality evidence. 7
Atypical antipsychotic augmentation (aripiprazole, quetiapine, brexpiprazole) achieves remission in approximately one-third of SSRI non-responders, but requires metabolic and extrapyramidal monitoring. 7
Repetitive transcranial magnetic stimulation (rTMS) or electroconvulsive therapy (ECT) are recommended for multiple treatment failures or when rapid improvement is required. 7

Critical Clinical Pitfalls to Avoid

Dosing and Timing Errors

Do not administer the second Auvelity dose after 3 PM, as late-day dosing significantly increases insomnia risk. 3
Do not exceed the maximum dose of 90 mg dextromethorphan/210 mg bupropion daily, as seizure risk rises markedly above this threshold. 3

Contraindication Oversights

Do not prescribe Auvelity without screening for seizure history, eating disorders, uncontrolled hypertension, and recent MAOI use, as these contraindications are absolute. 3
Do not combine Auvelity with other medications that lower seizure threshold (e.g., antipsychotics, tramadol, stimulants) without extreme caution. 3

Monitoring Failures

Do not skip the intensive monitoring window during weeks 1–2, as this period carries the highest risk for emergent suicidal ideation, especially in patients younger than 24 years. 3, 7
Do not fail to monitor blood pressure, particularly in the first 12 weeks, as bupropion-induced hypertension can develop insidiously. 3

Premature Discontinuation

Do not discontinue Auvelity before 6–8 weeks unless significant adverse effects occur, as premature switching leads to missed opportunities for response. 7
Do not abruptly stop Auvelity; taper gradually to minimize potential withdrawal symptoms, particularly if the patient has been on treatment for several months. 3

Practical Implementation

Patient Selection

Auvelity is particularly well-suited for patients who require rapid symptom relief (e.g., those with high suicide risk, severe functional impairment, or prior slow response to SSRIs). 1
Consider Auvelity for patients concerned about SSRI-related sexual dysfunction or weight gain, as the bupropion component mitigates these side effects. 3
Use Auvelity as add-on therapy in patients with partial response to an SSRI or SNRI, as real-world data show 71.2% of patients use it in combination. 5

Switching Strategies

When switching from an SSRI to Auvelity, no washout period is required (unlike MAOIs, which require 14 days). 3
When switching from bupropion monotherapy to Auvelity, the transition is straightforward, as the bupropion dose in Auvelity (105 mg twice daily = 210 mg/day) is within the therapeutic range. 3

Cost and Access Considerations

Auvelity is a branded medication without generic alternatives, making it more expensive than generic SSRIs or bupropion; prior authorization may be required by insurers. 5
Real-world adoption has been rapid, with over 22,000 patients initiating Auvelity within one year of FDA approval, indicating growing acceptance despite cost. 5

How should Auvelity (dextromethorphan/bupropion) be dosed and monitored, what are its contraindications and common adverse effects, and what alternative treatments are available for major depressive disorder in adults?

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