Friedrich MJ. Depression is the leading cause of disability around the world. JAMA. 2017;317:1517. https://doi.org/10.1001/jama.2017.3826.

Article  PubMed  Google Scholar 

GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1789–858. https://doi.org/10.1016/S0140-6736(18)32279-7.

Article  Google Scholar 

Lam RW, McIntosh D, Wang J, Enns MW, Kolivakis T, Michalak EE, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 1. Disease Burden and Principles of Care. Can J Psychiatry. 2016;61:510–23. https://doi.org/10.1177/0706743716659416.

Maj M, Stein DJ, Parker G, Zimmerman M, Fava GA, De Hert M, et al. The clinical characterization of the adult patient with depression aimed at personalization of management. World Psychiatry. 2020;19:269–93. https://doi.org/10.1002/wps.20771.

Article  PubMed  PubMed Central  Google Scholar 

Rhee TG, Steffens DC. Major depressive disorder and impaired health-related quality of life among US older adults. Int J Geriatr Psychiatry. 2020;35:1189–97. https://doi.org/10.1002/gps.5356.

Article  PubMed  Google Scholar 

McIntyre RS, Millson B, Power GS. Burden of Treatment Resistant Depression (TRD) in patients with major depressive disorder in Ontario using Institute for Clinical Evaluative Sciences (ICES) databases: economic burden and healthcare resource utilization. J Affect Disord. 2020;277:30–8. https://doi.org/10.1016/j.jad.2020.07.045.

Article  PubMed  Google Scholar 

Berton O, Nestler EJ. New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci. 2006;7:137–51. https://doi.org/10.1038/nrn1846.

Article  CAS  PubMed  Google Scholar 

Hermida AP, Glass OM, Shafi H, McDonald WM. Electroconvulsive therapy in depression: current practice and future direction. Psychiatr Clin North Am. 2018;41:341–53. https://doi.org/10.1016/j.psc.2018.04.001.

Article  PubMed  Google Scholar 

Rhee TG, Shim SR, Forester BP, Nierenberg AA, McIntyre RS, Papakostas GI, et al. Efficacy and safety of ketamine vs electroconvulsive therapy among patients with major depressive episode: a systematic review and meta-analysis. JAMA Psychiat. 2022;79:1162–72. https://doi.org/10.1001/jamapsychiatry.2022.3352.

Article  Google Scholar 

McIntyre RS, Filteau M-J, Martin L, Patry S, Carvalho A, Cha DS, et al. Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect Disord. 2014;156:1–7. https://doi.org/10.1016/j.jad.2013.10.043.

Article  CAS  PubMed  Google Scholar 

Zhdanava M, Pilon D, Ghelerter I, Chow W, Joshi K, Lefebvre P, et al. The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States. J Clin Psychiatry. 2021;82:20m13699. https://doi.org/10.4088/JCP.20m13699.

Article  PubMed  Google Scholar 

Jaffe DH, Rive B, Denee TR. The humanistic and economic burden of treatment-resistant depression in Europe: a cross-sectional study. BMC Psychiatry. 2019;19:247. https://doi.org/10.1186/s12888-019-2222-4.

Article  PubMed  PubMed Central  Google Scholar 

Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67:793–802. https://doi.org/10.1001/archgenpsychiatry.2010.90.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hofmann SG, Curtiss J, Carpenter JK, Kind S. Effect of treatments for depression on quality of life: a meta-analysis. Cogn Behav Ther. 2017;46:265–86. https://doi.org/10.1080/16506073.2017.1304445.

Article  PubMed  PubMed Central  Google Scholar 

McIntyre RS, Cha DS, Soczynska JK, Woldeyohannes HO, Gallaugher LA, Kudlow P, et al. Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions. Depress Anxiety. 2013;30:515–27. https://doi.org/10.1002/da.22063.

Article  PubMed  Google Scholar 

Alnefeesi Y, Chen-Li D, Krane E, Jawad MY, Rodrigues NB, Ceban F, et al. Real-world effectiveness of ketamine in treatment-resistant depression: a systematic review and meta-analysis. J Psychiatr Res. 2022;151:693–709. https://doi.org/10.1016/j.jpsychires.2022.04.037.

Article  PubMed  Google Scholar 

Marcantoni WS, Akoumba BS, Wassef M, Mayrand J, Lai H, Richard-Devantoy S, et al. A systematic review and meta-analysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009–January 2019. J Affect Disord. 2020;277:831–41. https://doi.org/10.1016/j.jad.2020.09.007.

Article  CAS  PubMed  Google Scholar 

McIntyre RS, Rosenblat JD, Nemeroff CB, Sanacora G, Murrough JW, Berk M, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry. 2021;178:383–99. https://doi.org/10.1176/appi.ajp.2020.20081251.

Article  PubMed  PubMed Central  Google Scholar 

Yavi M, Lee H, Henter ID, Park LT, Zarate CA. Ketamine treatment for depression: a review. Discov Ment Health. 2022;2:9. https://doi.org/10.1007/s44192-022-00012-3.

Article  PubMed  PubMed Central  Google Scholar 

Majeed A, Xiong J, Teopiz KM, Ng J, Ho R, Rosenblat JD, 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. https://doi.org/10.1080/14728214.2021.1898588.

Article  CAS  PubMed  Google Scholar 

Nguyen L, Thomas KL, Lucke-Wold BP, Cavendish JZ, Crowe MS, Matsumoto RR. Dextromethorphan: an update on its utility for neurological and neuropsychiatric disorders. Pharmacol Ther. 2016;159:1–22. https://doi.org/10.1016/j.pharmthera.2016.01.016.

Article  CAS  PubMed  Google Scholar 

Hole K, Arnestad M, Molden E, Haslemo T. Dose-dependent inhibition of cYP2D6 by bupropion in patients with depression. J Clin Psychopharmacol. 2021;41:281–5. https://doi.org/10.1097/JCP.0000000000001387.

Article  CAS  PubMed  Google Scholar 

O’Gorman C, Jones A, Tabuteau H. AXS-05 (Dextromethorphan/Bupropion): psychopharmacology and the potential for therapeutic application in the treatment of neuropsychiatric symptoms. Eur Neuropsychopharmacol. 2019;29:S458. https://doi.org/10.1016/j.euroneuro.2018.11.686.

Article  Google Scholar 

Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. https://doi.org/10.1136/bmj.d5928.

Article  PubMed  PubMed Central  Google Scholar 

Tabuteau H, Jones A, Anderson A, Jacobson M, Iosifescu DV. Effect of AXS-05 (Dextromethorphan-Bupropion) in major depressive disorder: a randomized double-blind controlled trial. Am J Psychiatry. 2022;179:490–9. https://doi.org/10.1176/appi.ajp.21080800.

Article  PubMed  Google Scholar 

Iosifescu DV, Jones A, O’Gorman C, Streicher C, Feliz S, Fava M, 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. https://doi.org/10.4088/JCP.21m14345.

Article  PubMed  Google Scholar 

Jones A, O'Gorman C, Clayton AH, Tabuteau H. Analysis of Efficacy of AXS-05 in the Treatment of Major Depressive Disorder Based on Gender, Race, and Prior Antidepressant Use [Poster Presentation]. ISCTM Annual Meeting, New York, NY, USA; April 6-9 2021. https://isctm.org/public_access/17th_Annual/Poster/Jones_poster.pdf.

O'Gorman C, Jones A, Kennon K, Niecestro R, Iosifescu DV, Stahl S, et al. AXS-05 for Neuropsychiatric Disorders: Scientific Rationale and Clinical Development [Poster Presentation]. ASCP Annual Meeting, Miami Beach, FL, USA. May 29-June 1 2018. https://d3dyybxyjb4kyh.cloudfront.net/pdfs/Axsome_AXS_05_Poster_ASCP_5_2018.pdf.

O'Gorman C, Jones A, Tabuteau H. Sustained Efficacy with Long-term Treatment if AXS-05: Results from the COMET Phase 3 Trial, a Long-term, Open-label Study Evaluating the Efficacy and Safety of AXS-05 for the Treatment of MDD [Poster Presentation]. American Society of Clinical Psychopharmacology, Annual Meeting, New York, NY, USA. June 1-4 2021. https://d3dyybxyjb4kyh.cloudfront.net/pdfs/ASCP+2021+COMET+overall+poster+FINAL.pdf

Matveychuk D, Thomas RK, Swainson J, Khullar A, MacKay M-A, Baker GB, et al. Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers. Ther Adv Psychopharmacol. 2020;10:2045125320916657. https://doi.org/10.1177/2045125320916657.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rodrigues NB, McIntyre RS, Lipsitz O, Cha DS, Lee Y, Gill H, et al. Changes in symptoms of anhedonia in adults with major depressive or bipolar disorder receiving IV ketamine: results from the Canadian Rapid Treatment Center of Excellence. J Affect Disord. 2020;276:570–5. https://doi.org/10.1016/j.jad.2020.07.083.

Article  CAS  PubMed  Google Scholar 

Siu A, Drachtman R. Dextromethorphan: a review of N-methyl-d-aspartate receptor antagonist in the management of pain. CNS Drug Rev. 2007;13:96–106. https://doi.org/10.1111/j.1527-3458.2007.00006.x.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zanger UM, Raimundo S, Eichelbaum M. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol. 2004;369:23–37. https://doi.org/10.1007/s00210-003-0832-2.

Article  CAS  PubMed  Google Scholar 

Xue C, Zhang X, Cai W. Prediction of drug–drug interactions with bupropion and its metabolites as CYP2D6 inhibitors using a physiologically-based pharmacokinetic model. Pharmaceutics. 2017;10:1. https://doi.org/10.3390/pharmaceutics10010001.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Garnock-Jones KP. Dextromethorphan/quinidine: in pseudobulbar affect. CNS Drugs. 2011;25:435–45. https://doi.org/10.1016/j.jad.2020.07.083.

Article  CAS  PubMed  Google Scholar 

Taylor CP, Traynelis SF, Siffert J, Pope LE, Matsumoto RR. Pharmacology of dextromethorphan: relevance to dextromethorphan/quinidine (Nuedexta®) clinical use. Pharmacol Ther. 2016;164:170–82. https://doi.org/10.1016/j.pharmthera.2016.04.010.