Clinical Overview: Auvelity (Dextromethorphan and Bupropion) for Major Depressive Disorder

Background

Major depressive disorder (MDD) is diagnosed using the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria, which includes symptoms such as depressed mood, loss of interest or pleasure, weight loss or gain, insomnia or hypersomnia, agitation, fatigue, feelings of worthlessness, decreased concentration, and thoughts of death or suicide.

With an abundance of medications and different classes of medications used in the treatment of MDD, pharmacists play a major role and can have a large impact on patients’ lives, from counseling on medications to assisting physicians and patients with finding the right medication. Because pharmacists are the medication experts, it is important that we are educated about the new depression medication, dextromethorphan and bupropion (Auvelity), so we are comfortable with counseling and recommending this medication to treat our patient's depression.

Indication

In August 2022, Axsome Therapeutics achieved FDA approval for the first of its kind antidepressant sold under the brand name of Auvelity, which is a combination of the FDA-approved medications dextromethorphan and bupropion. Auvelity is indicated for the treatment of MDD in adults.

Mechanism of Action

This new antidepressant has a unique mechanism of action and is the only rapid-acting oral treatment for MDD. Dextromethorphan is an uncompetitive N-methyl-d-aspart (NMDA) receptor antagonist, which increases glutamate.

Dextromethorphan is also an agonist at the sigma-1 receptor, which increases serotonin levels. Bupropion blocks reuptake of norepinephrine and dopamine, which increases availability. It also acts as an inhibitor of CYP2D6, which then increases the concentration of dextromethorphan.

Dosing and Administration

Auvelity is an extended-release tablet containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride.

• Initial dosing: 1 tablet daily in the morning.
• Maintenance dosing: After 3 days, increase to the maximum dose of 2 tablets daily given at least 8 hours apart.
• Concomitant CYP2D6 inhibitor: Reduce dose to 1 tablet daily.

It is recommended to assess patient’s blood pressure periodically and ensure patients are not taking other medications containing bupropion or OTC medications containing dextromethorphan.

Dose Adjustments

Renal impairment:

• eGFR 30-59 mL/minute/1.73m²: Reduce dose to once daily in the morning
• eGFR is < 30 mL/minute/1.73m²: Avoid use

Most Common Adverse Effects (≥2% incidence)

Dizziness, nausea, headache, diarrhea, somnolence, sexual dysfunction, and more.

Black Box Warnings and Contraindications

Because Auvelity contains bupropion, there is a black box warning for increased risk of suicidal thoughts and behaviors in pediatric patients and young adults and is contraindicated in those with a seizure disorder, bulimia, or anorexia. It is also contraindicated to abruptly discontinue alcohol, benzodiazepines, barbiturates, and epileptic drugs while on this medication or use with an MOAI or within 14 days of discontinuation.

Efficacy

The efficacy was based on the GEMINI phase 3, randomized, placebo-controlled clinical trial.

Primary Efficacy Outcome

Measured the change in depression symptoms from baseline to week 6 according to the Montgomery-Asberg Depression Rating Scale (MADRS):

• 95% CI (-1.39 to -6.36); P = 0.002
• The mean change in MADRS total score was statistically significant with Auvelity reducing the score by 15.9 points compared to 12 points for placebo.

Secondary Efficacy Outcomes

Change in MADRS score from baseline at week 1:

• 95% CI (-0.6 to –3.9); P = 0.007
• The mean change in MADRS score from baseline to week 1 was statistically significant with Auvelity, reducing the score by 7.2 points compared to 5 points for placebo.

Change in MADRS score from baseline at week 2:

• 95% CI (-1.4 - -5.5); P = <0.001
• The mean change in MADRS score from baseline to week 2 was statistically significant with Auvelity, reducing the score by 11.1 points compared to 7.7 points for placebo.

Clinical response measured as a ≥ 50% reduction in MADRS total score at week 6:

• 95% CI (8.4% to 31.6%); P = < 0.001
• Clinical response measured as ≥50% reduction in MADRS score was statistically significant with 54% of Auvelity responders compared to 34% for placebo.

Overall, there is evidence that dextromethorphan and bupropion together lead to improvements in patient’s depressive symptoms and may be a viable option for those struggling to find the right medication.

About the Author

Seth Kriha, PharmD, PGY1 Pharmacy Resident, Mayo Clinic Health System — Mankato.

Preceptor: Chelsea Morken, PharmD, PGY2 Ambulatory Care Pharmacy Resident, Mayo Clinic Health System — Mankato.

References

1. Auvelity [Prescribing Information]. Axsome Therapeutics, Inc.: New York, NY
2. Iosifescu, D. V., Jones, A., O'Gorman, C., Streicher, C., Feliz, S., Fava, M., & Tabuteau, H. (2022). Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI). The Journal of clinical psychiatry, 83(4), 21m14345. https://doi.org/10.4088/JCP.21m14345
3. Stahl, S. (2019). Dextromethorphan/Bupropion: A Novel Oral NMDA (N-methyl-d-aspartate) Receptor Antagonist with Multimodal Activity. CNS Spectrums, 24(5), 461-466. doi:10.1017/S1092852919001470.