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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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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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Author information

Authors and Affiliations

  1. Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, ON, Canada

    Dania Akbar, Felicia Ceban, Angela T. H. Kwan & Joshua D. Rosenblat

  2. Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA

    Taeho Greg Rhee

  3. VA New England Mental Illness, Research, Education and Clinical Center (MIRECC), VA Connecticut Healthcare System, West Haven, CT, USA

    Taeho Greg Rhee

  4. Department of Public Health Sciences, University of Connecticut School of Medicine, Farmington, CT, USA

    Taeho Greg Rhee

  5. Brain and Cognition Discovery Foundation (BCDF), 77 Bloor St W Suite 617, Toronto, ON, M5S 1M2, Canada

    Felicia Ceban, Kayla M. Teopiz, Mehala Subramaniapillai, Angela T. H. Kwan & Roger S. McIntyre

  6. Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada

    Felicia Ceban

  7. Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Roger Ho

  8. Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore, Singapore

    Roger Ho

  9. Key Laboratory of Cognition and Personality, Faculty of Psychology, Ministry of Education, Southwest University, Chongqing, 400715, People’s Republic of China

    Bing Cao

  10. Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada

    Angela T. H. Kwan

  11. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Joshua D. Rosenblat & Roger S. McIntyre

  12. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada

    Roger S. McIntyre

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  1. Dania Akbar
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Correspondence to Roger S. McIntyre.

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This research did not receive any grants from funding agencies in the public, commercial, or not-for-profit sectors.

Conflicts of interest

Dr. Taeho Gregory Rhee was supported in part by the National Institute on Aging (NIA) through Yale School of Medicine (#T32AG019134) in the past 3 years. Dr. Rhee has also been funded by the NIA (#R21AG070666), National Institute of Mental Health (#R21MH117438) and Institute for Collaboration on Health, Intervention, and Policy (InCHIP) of the University of Connecticut. Dr. Rhee serves as a review committee member for Patient-Centered Outcomes Research Institute (PCORI) and Substance Abuse and Mental Health Services Administration (SAMHSA) and has received honoraria payments from PCORI and SAMHSA. Dr. Rhee has also served as a stakeholder/consultant for PCORI and received consulting fees from PCORI. Dr. Rhee serves as an advisory committee member for International Alliance of Mental Health Research Funders (IAMHRF). Dr. Rhee is currently a co-editor-in-chief of Mental Health Science and has received honorarium payments annually from the publisher, John Wiley & Sons, Inc. Kayla M. Teopiz has received personal fees from Braxia Scientific Corp. Dr. Roger S. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes,Neumora Therapeutics, Boehringer Ingelheim,Sage,Biogen,Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals,Viatris, Abbvie, Atai Life Sciences. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp. Drs Akbar, Ceban, Ho, Cao, Subramaniapillai, Kwan and Rosenblat have no conflicts of interest to declare.

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Authors’ contributions

DA: data curation, investigation, project administration, visualization, writing—original draft. TGR: writing—review and editing. FC: writing—review and editing. RH: writing—review and editing. KMT: writing—review and editing. BC: writing—review and editing. MS: writing—review and editing. ATHK: writing—review and editing. JDR: writing—review and editing. RSM: conceptualization, project administration, visualization, supervision, writing—review and editing. All authors have read and approve the final version of this manuscript and agree to be accountable for the work.

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Akbar, D., Rhee, T.G., Ceban, F. et al. Dextromethorphan-Bupropion for the Treatment of Depression: A Systematic Review of Efficacy and Safety in Clinical Trials. CNS Drugs 37, 867–881 (2023). https://doi.org/10.1007/s40263-023-01032-5

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