World Health Organization. Depression and other common mental disorders. Global health estimates. 2017. Available at: https://www.who.int/publications/i/item/depression-global-health-estimates.

Santomauro DF, Herrera AMM, Shadid J, et al. Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic. Lancet. 2021;398:1700–12.

Article  Google Scholar 

Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391:1357–66.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rush AJ, Kraemer HC, Sackeim HA, et al. Report by the ACNP task force on response and remission in major depressive disorder. Neuropsychopharmacology. 2006;31:1841–53.

Article  PubMed  Google Scholar 

Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.

Article  PubMed  Google Scholar 

Pigott HE, Kim T, Xu C, Kirsch I, Amsterdam J. What are the treatment remission, response and extent of improvement rates after up to four trials of antidepressant therapies in real-world depressed patients? A reanalysis of the STAR*D study’s patient-level data with fidelity to the original research protocol. BMJ Open. 2023;13: e063095.

Article  PubMed  PubMed Central  Google Scholar 

Sheehan DV, Harnett-Sheehan K, Spann ME, Thompson HF, Prakash A. Assessing remission in major depressive disorder and generalized anxiety disorder clinical trials with the discan metric of the Sheehan Disability Scale. Int Clin Psychopharmacol. 2011;26:75–83.

Article  PubMed  Google Scholar 

Kubitz N, Vossen C, Papadimitropoulou K, Karabis A. The prevalence and disease burden of treatment-resistant depression—a systematic review of the literature. Value Health. 2014;17:A455–6.

Article  CAS  PubMed  Google Scholar 

McIntyre RS, Alsuwaidan M, Baune BT, et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023;22:394–412.

Article  PubMed  PubMed Central  Google Scholar 

Fekadu A, Wooderson SC, Markopoulo K, Donaldson C, Papadopoulos A, Cleare AJ. What happens to patients with treatment-resistant depression? A systematic review of medium to long term outcome studies. J Affect Disord. 2009;116:4–11.

Article  PubMed  Google Scholar 

Brenner P, Reutfors J, Nijs M, Andersson TM. Excess deaths in treatment-resistant depression. Ther Adv Psychopharmacol. 2021;11:20451253211006508.

Article  PubMed  PubMed Central  Google Scholar 

Lundberg J, Cars T, Lööv SÅ, et al. Association of treatment-resistant depression with patient outcomes and health care resource utilization in a population-wide study. JAMA Psychiat. 2023;80:167–75.

Article  Google Scholar 

Corral R, Alessandria H, Baena LMA, et al. Suicidality and quality of life in treatment-resistant depression patients in Latin America: secondary interim analysis of the TRAL study. Front Psychiatry. 2022;13: 812938.

Article  PubMed  PubMed Central  Google Scholar 

Kern DM, Canuso CM, Daly E, et al. Suicide-specific mortality among patients with treatment-resistant major depressive disorder, major depressive disorder with prior suicidal ideation or suicide attempts, or major depressive disorder alone. Brain Behav. 2023;13: e3171.

Article  PubMed  PubMed Central  Google Scholar 

Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry. 2003;160:1516–8.

Article  PubMed  Google Scholar 

Castrén E. Is mood chemistry? Nat Rev Neurosci. 2005;6:241–6.

Article  PubMed  Google Scholar 

Castrén E, Monteggia LM. Brain-derived neurotrophic factor signaling in depression and antidepressant action. Biol Psychiatry. 2021;90:128–36.

Article  PubMed  Google Scholar 

Page CE, Epperson CN, Novick AM, Duffy KA, Thompson SM. Beyond the serotonin deficit hypothesis: communicating a neuroplasticity framework of major depressive disorder. Mol Psychiatry. 2024;29:3802–13.

Article  PubMed  Google Scholar 

European Medicines Agency. Spravato. Summary of product characteristics. 2024. Available at: https://www.ema.europa.eu/en/documents/product-information/spravato-epar-product-information_en.pdf.

Bahr R, Lopez A, Rey JA. Intranasal esketamine (Spravato™) for use in treatment-resistant depression in conjunction with an oral antidepressant. P T. 2019;44:340–75.

PubMed  PubMed Central  Google Scholar 

Duman RS, Deyama S, Fogaça MV. Role of BDNF in the pathophysiology and treatment of depression: activity-dependent effects distinguish rapid-acting antidepressants. Eur J Neurosci. 2021;53:126–39.

Article  CAS  PubMed  Google Scholar 

Food and Drug Administration. SPRAVATO Prescribing Information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/211243s015lbl.pdf. 2024.

Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019;22:616–30.

Article  PubMed  PubMed Central  Google Scholar 

Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176:428–38.

Article  PubMed  Google Scholar 

Ochs-Ross R, Daly EJ, Zhang Y, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression-TRANSFORM-3. Am J Geriatr Psychiatry. 2020;28:121–41.

Article  PubMed  Google Scholar 

Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiat. 2019;76:893–903.

Article  Google Scholar 

Wajs E, Aluisio L, Holder R, et al. Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2). J Clin Psychiatry. 2020;81:19m12891.

Article  PubMed  Google Scholar 

Turkoz I, Daly E, Singh J, et al. Treatment response with esketamine nasal spray plus an oral antidepressant in patients with treatment-resistant depression without evidence of early response: a pooled post hoc analysis of the TRANSFORM studies. J Clin Psychiatry. 2021;82:20m13800.

Article  PubMed  Google Scholar 

European Medicines Agency. First union list of critical medicines. 2023. Available at: https://ec.europa.eu/commission/presscorner/detail/en/ip_23_6377.

Boudieu L, Mennetrier M, Llorca P-M, Samalin L. The efficacy and safety of intranasal formulations of Ketamine and Esketamine for the treatment of major depressive disorder: a systematic review. Pharmaceutics. 2023;15(12):2773.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340: c332.

Article  PubMed  PubMed Central  Google Scholar 

Rothwell PM. External validity of randomised controlled trials: “to whom do the results of this trial apply?” Lancet. 2005;365:82–93.

Article  PubMed  Google Scholar 

Kennedy-Martin T, Curtis S, Faries D, Robinson S, Johnston J. A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results. Trials. 2015;16:495.

Article  PubMed  PubMed Central  Google Scholar 

Agencia Española de Medicamentos y Productos Sanitarios. Informe de posicionamiento terapéutico de esketamina (Spravato®) en trastorno depresivo mayor resistente al tratamiento. 2022. Available at: https://www.aemps.gob.es/medicamentosUsoHumano/informesPublicos/docs/2022/IPT_17-2022-Spravato.pdf.

Lobo A, Chamorro L, Luque A, Dal-Ré R, Badia X, Baró E. Validación de las versiones en español de la Montgomery-Asberg Depression Rating Scale y la Hamilton Anxiety Rating Scale para la evaluación de la depresión y de la ansiedad. Med Clín. 2002;118:493–9.

Article  Google Scholar 

Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382–9.

Article  CAS  PubMed  Google Scholar 

Luciano JV, Bertsch J, Salvador-Carulla L, et al. Factor structure, internal consistency and construct validity of the Sheehan Disability Scale in a Spanish primary care samp