Dextromethorphan/Bupropion (Auvelity)
October 30, 2022 4 minutes read
By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved a combination of dextromethorphan (DXM) and bupropion (BUP) to treat major depressive disorder in adults. DXM is a N-methyl-d-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist. BUP, a CYP2D6 inhibitor, is a commonly used antidepressant. BUP slows the metabolism of DXM, increases its plasma level, and provides antidepressants with different modes of action. The FDA granted DXM/BUP a priority review and breakthrough designation. It will be distributed as Auvelity.
INDICATIONS
DXM/BUP can be prescribed to treat major depressive disorder in adults.1
DOSAGE
The recommended starting dose is one tablet in the morning.1 After three days, increase the dose to one tablet twice daily, separated by at least eight hours.
The dose is one tablet in the morning for patients with moderate renal impairment or who are poor CYP2D6 metabolizers. DXM/BUP is available as extended-release tablets, each containing 45 mg of DXM and 105 mg of BUP.
POTENTIAL ADVANTAGES
DXM/BUP provides a multimodal approach to treating major depressive disorder, as the combination targets the serotonin, norepinephrine, dopamine, and glutamate systems. This solution also has demonstrated pharmacologic synergy.1-3 Auvelity onsets relatively rapidly, with detectable benefits as early as week 1.1,4 In clinical trials, DXM/BUP was not associated with weight gain or more sexual dysfunction.4,5
POTENTIAL DISADVANTAGES
DXM/BUP shares the same boxed warning as other antidepressants — for suicidal thoughts and behavior in pediatric and young adults.1 It is not indicated for pediatric patients.
Other warnings and precautions include dose-related seizure risk, higher blood pressure, activation of mania or hypomania, angle-closure glaucoma, embryo-fetal toxicity, serotonin syndrome, and psychosis and other neuropsychiatric reactions.1 The most common adverse reactions are dizziness (16%), headache (8%), diarrhea (7%), somnolence (7%), dry mouth (6%), sexual dysfunction (6%), and hyperhidrosis (5%).1
COMMENTS
The efficacy of DXM/BUP was demonstrated in two six-week studies: a placebo-controlled study (study 1) and a study compared with the BUP component alone (study 2).1,4,5 Subjects with psychotic/psychiatric disorders, alcohol/substance use disorders, significant medical comorbidities, and significant risk of suicide were excluded.4,5
In study 1, subjects with major depressive disorder were randomized to DXM/BUP (n = 157) or placebo (n = 162).1,4 The primary endpoint was the change from baseline to week 6 in the Montgomery-Åsberg Depression Rating Scale (MADRS). The mean baseline score was 33.8 for DXM/BUP and 33.2 for placebo. The overall mean difference from baseline to week 6 was -3.9 (95% confidence interval [CI], -6.4 to -1.4). Remission (MADRS score ≤ 10) and clinical response (50% improvement) at week 6 were 40% vs. 17% and 54% vs. 34%, respectively. Significant differences (vs. placebo) in MADRS were observed in week 1, while remission and clinical response were detected by week 2.2
Study 2 demonstrated the benefit of DXM/BUP over BUP alone and pharmacological synergy.5 Major depressive disorder subjects were randomized to either DXM/BUP (n = 43) or BUP only at the same dose (n = 37). The overall mean effect difference was -4.9 (95% CI, -3.1 to -6.8), with significant difference seen at week 2. Importantly, the dose of BUP (210 mg) was lower than the target dose (300 mg) of BUP as monotherapy.5
CLINICAL IMPLICATIONS
Major depressive disorder is a prevalent, disabling, chronic disorder that significantly affects quality of life. There are many antidepressants available with varying mechanisms of action; however, there are numerous shortcomings. A significant portion of patients fail to respond, with a remission rate of 37% after the first treatment. Those who respond often do so after six weeks of treatment.6,7
Here, DXM, which produces a similar mode of action as ketamine and esketamine, is combined with BUP to provide a multimodal mechanism of action and (possibly) a faster onset of action vs. mono-component therapy. DXM/BUP is expected to be available in the fourth quarter of 2022.
REFERENCES
1. Axsome Therapeutics, Inc. Auvelity prescribing information. August 2022.
2. Stahl SM. Dextromethorphan/bupropion: A novel oral NMDA (N-methyl-d-aspartate) receptor antagonist with multimodal activity. CNS Spectr 2019;24:461-466.
3. Majeed A, et al. Efficacy of dextromethorphan for the treatment of depression: A systematic review of preclinical and clinical trials. Expert Opin Emerg Drugs 2021;26:63-74.
4. Iosifescu DV, et al. Efficacy and safety of AXS-05 (dextromethorphan-bupropion) in patients with major depressive disorder: A phase 3 randomized clinical trial (GEMINI). J Clin Psychiatry 2022;83:21m14345.
5. Tabuteau H, et al. Effect of AXS-05 (dextromethorphan-bupropion) in major depressive disorder: A randomized double-blind controlled trial. Am J Psychiatry 2022;179:490-499.
6. Rush AJ. STAR*D: What have we learned? Am J Psychiatry 2007;164:201-204.
7. Rush AJ, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry 2006;163:1905-1917.
Auvelity can be prescribed to treat major depressive disorder in adults.
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