Dextromethorphan-Bupropion for the Treatment of Depression: A Systematic Review of Efficacy and Safety in Clinical Trials

Dania Akbar¹, Taeho Greg Rhee^{2

3

4}, Felicia Ceban^{1

5

6}, Roger Ho^{7

8}, Kayla M Teopiz⁵, Bing Cao⁹, Mehala Subramaniapillai⁵, Angela T H Kwan^{1

5

10}, Joshua D Rosenblat^{1

11}, Roger S McIntyre^{12

13

14}

Affiliations

¹ Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, ON, Canada.
² Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
³ VA New England Mental Illness, Research, Education and Clinical Center (MIRECC), VA Connecticut Healthcare System, West Haven, CT, USA.
⁴ Department of Public Health Sciences, University of Connecticut School of Medicine, Farmington, CT, USA.
⁵ Brain and Cognition Discovery Foundation (BCDF), 77 Bloor St W Suite 617, Toronto, ON, M5S 1M2, Canada.
⁶ Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada.
⁷ Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁸ Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore, Singapore.
⁹ Key Laboratory of Cognition and Personality, Faculty of Psychology, Ministry of Education, Southwest University, Chongqing, 400715, People's Republic of China.
¹⁰ Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
¹¹ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
¹² Brain and Cognition Discovery Foundation (BCDF), 77 Bloor St W Suite 617, Toronto, ON, M5S 1M2, Canada. roger.mcintyre@bcdf.org.
¹³ Department of Psychiatry, University of Toronto, Toronto, ON, Canada. roger.mcintyre@bcdf.org.
¹⁴ Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. roger.mcintyre@bcdf.org.

PMID: 37792265
DOI: 10.1007/s40263-023-01032-5

Dextromethorphan-Bupropion for the Treatment of Depression: A Systematic Review of Efficacy and Safety in Clinical Trials

Dania Akbar et al. CNS Drugs. 2023 Oct.

. 2023 Oct;37(10):867-881.

doi: 10.1007/s40263-023-01032-5. Epub 2023 Oct 4.

Authors

Affiliations

¹ Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, ON, Canada.
² Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
³ VA New England Mental Illness, Research, Education and Clinical Center (MIRECC), VA Connecticut Healthcare System, West Haven, CT, USA.
⁴ Department of Public Health Sciences, University of Connecticut School of Medicine, Farmington, CT, USA.
⁵ Brain and Cognition Discovery Foundation (BCDF), 77 Bloor St W Suite 617, Toronto, ON, M5S 1M2, Canada.
⁶ Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada.
⁷ Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁸ Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore, Singapore.
⁹ Key Laboratory of Cognition and Personality, Faculty of Psychology, Ministry of Education, Southwest University, Chongqing, 400715, People's Republic of China.
¹⁰ Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
¹¹ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
¹² Brain and Cognition Discovery Foundation (BCDF), 77 Bloor St W Suite 617, Toronto, ON, M5S 1M2, Canada. roger.mcintyre@bcdf.org.
¹³ Department of Psychiatry, University of Toronto, Toronto, ON, Canada. roger.mcintyre@bcdf.org.
¹⁴ Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. roger.mcintyre@bcdf.org.

PMID: 37792265
DOI: 10.1007/s40263-023-01032-5

Abstract

Background: A significant proportion of adults with major depressive disorder (MDD) do not respond to treatments which are currently used in clinical practice such as first-generation monoamine-based antidepressants.

Objectives: The objective of this systematic review was to assess the efficacy, safety, and mechanisms of action of AXS-05, a combination of the NMDA-receptor antagonist dextromethorphan with bupropion, in adults with MDD.

Methods: We searched PubMed, Embase, Google Scholar, and ClinicalTrials.gov for current studies reporting on efficacy and/or safety of AXS-05 in patients with MDD. The search terms included: "AXS-05" OR "dextromethorphan and bupropion" AND "depression". Studies from database inception to January 2023 were evaluated. Risk of bias was assessed using the Cochrane Risk of Bias tool.

Results: The search yielded 54 studies of which 5 were included. All studies had low risk of bias. Depression severity, measured with the Montgomery-Åsberg Depression Rating Scale (MADRS) significantly decreased as early as 1-week post-treatment from baseline when compared to a placebo-controlled group (LS mean difference 2.2; 95% CI 0.6-3.9; p = 0.007) and at 2 weeks compared to an active control group (LS mean difference 4.7; 95% CI 0.6-8.8; p = 0.024). Treatment efficacy could be maintained for up to 12 months with mean MADRS score reduction of 23 points from baseline. Clinical remission and response rates also improved at week 1 and were maintained for 12 months. The treatment was well-tolerated, with some transient adverse events reported.

Conclusion: Current evidence suggests that the combination of dextromethorphan and bupropion is a well-tolerated, rapid-acting treatment option for adults with MDD. Initial success with AXS-05 supports the mechanistic role of glutamatergeric and sigma 1 signaling in the pathophysiology of MDD.

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References

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Dextromethorphan-Bupropion for the Treatment of Depression: A Systematic Review of Efficacy and Safety in Clinical Trials

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Dextromethorphan-Bupropion for the Treatment of Depression: A Systematic Review of Efficacy and Safety in Clinical Trials

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