Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA (2022) The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry https://doi.org/10.1038/s41380-022-01661-0

Article  PubMed  Google Scholar 

Jakobsen JC, Gluud C, Kirsch I (2020) Should antidepressants be used for major depressive disorder? BMJ Evid Based Med 25:130–130. https://doi.org/10.1136/bmjebm-2019-111238

Article  PubMed  Google Scholar 

Mathews DC, Henter ID, Zarate CA (2012) Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date. Drugs 72:1313–1333. https://doi.org/10.2165/11633130-000000000-00000

Article  CAS  PubMed  PubMed Central  Google Scholar 

Boku S, Nakagawa S, Toda H, Hishimoto A (2018) Neural basis of major depressive disorder: beyond monoamine hypothesis. Psychiatry Clin Neurosci 72:3–12. https://doi.org/10.1111/pcn.12604

Article  CAS  PubMed  Google Scholar 

Henter ID, de Sousa RT, Zarate CA Jr (2018) Glutamatergic modulators in depression. Harv Rev Psychiatry 26:307–319. https://doi.org/10.1097/HRP.0000000000000183

Article  PubMed  PubMed Central  Google Scholar 

Nicoll RA (2017) A brief history of long-term potentiation. Neuron 93:281–290. https://doi.org/10.1016/j.neuron.2016.12.015

Article  CAS  PubMed  Google Scholar 

Hansen KB, Yi F, Perszyk RE, Furukawa H, Wollmuth LP, Gibb AJ, Traynelis SF (2018) Structure, function, and allosteric modulation of NMDA receptors. J Gen Physiol 150:1081–1105. https://doi.org/10.1085/jgp.201812032

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mahati K, Bhagya V, Christofer T, Sneha A, Shankaranarayana Rao BS (2016) Enriched environment ameliorates depression-induced cognitive deficits and restores abnormal hippocampal synaptic plasticity. Neurobiol Learn Mem 134:379–391. https://doi.org/10.1016/j.nlm.2016.08.017

Article  PubMed  Google Scholar 

Bora E, Harrison BJ, Yücel M, Pantelis C (2013) Cognitive impairment in euthymic major depressive disorder: a meta-analysis. Psychol Med 43:2017–2026. https://doi.org/10.1017/S0033291712002085

Article  CAS  PubMed  Google Scholar 

Kim JJ, Diamond DM (2002) The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 3:453–462. https://doi.org/10.1038/nrn849

Article  CAS  PubMed  Google Scholar 

Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, Witztum J, Shaver DC, Rosenthal DL, Alway EJ, Lopez K, Meng Y, Nellissen L, Grosenick L, Milner TA, Deisseroth K, Bito H, Kasai H, Liston C (2019) Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science 364:eaat8078. https://doi.org/10.1126/science.aat8078

Article  CAS  PubMed  PubMed Central  Google Scholar 

Videbech P, Ravnkilde B (2004) Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry 161:1957–1966. https://doi.org/10.1176/appi.ajp.161.11.1957

Article  PubMed  Google Scholar 

Neumeister A, Wood S, Bonne O, Nugent AC, Luckenbaugh DA, Young T, Bain EE, Charney DS, Drevets WC (2005) Reduced hippocampal volume in unmedicated, remitted patients with major depression versus control subjects. Biol Psychiatry 57:935–937. https://doi.org/10.1016/j.biopsych.2005.01.016

Article  PubMed  Google Scholar 

Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329:959–964. https://doi.org/10.1126/science.1190287

Article  CAS  PubMed  PubMed Central  Google Scholar 

Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng P-f, Kavalali ET, Monteggia LM (2011) NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475:91–95. https://doi.org/10.1038/nature10130

Article  CAS  PubMed  PubMed Central  Google Scholar 

Fogaça MV, Fukumoto K, Franklin T, Liu R-J, Duman CH, Vitolo OV, Duman RS (2019) N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects. Neuropsychopharmacology 44:2230–2238. https://doi.org/10.1038/s41386-019-0501-x

Article  CAS  PubMed  PubMed Central  Google Scholar 

Stahl SM, De Martin S, Mattarei A, Bettini E, Pani L, Guidetti C, Folli F, de Somer M, Traversa S, Inturrisi CE (2022) Esmethadone (REL-1017) and other uncompetitive NMDAR channel blockers may improve mood disorders via modulation of synaptic kinase-mediated signaling. Int J Mol Sci 23:12196. https://doi.org/10.3390/ijms232012196

Article  CAS  PubMed  PubMed Central  Google Scholar 

Duman RS, Sanacora G, Krystal JH (2019) Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron 102:75–90. https://doi.org/10.1016/j.neuron.2019.03.013

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bonaventura J, Lam S, Carlton M, Boehm MA, Gomez JL, Solis O, Sanchez-Soto M, Morris PJ, Fredriksson I, Thomas CJ, Sibley DR, Shaham Y, Zarate CA Jr, Michaelides M (2021) Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability. Mol Psychiatry 26:6704–6722. https://doi.org/10.1038/s41380-021-01093-2

Article  CAS  PubMed  PubMed Central  Google Scholar 

Keam SJ (2022) Dextromethorphan/Bupropion: first approval. CNS Drugs 36:1229–1238. https://doi.org/10.1007/s40263-022-00968-4

Article  CAS  PubMed  Google Scholar 

Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, Mazzucco C, Hough D, Thase ME, Shelton RC, Molero P, Vieta E, Bajbouj M, Manji H, Drevets WC, Singh JB (2019) 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 176:428–438. https://doi.org/10.1176/appi.ajp.2019.19020172

Article  PubMed  Google Scholar 

Tabuteau H, Jones A, Anderson A, Jacobson M, Iosifescu DV (2022) Effect of AXS-05 (Dextromethorphan-Bupropion) in major depressive disorder: a randomized double-blind controlled trial. Am J Psychiatry 179:490–499. 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, Tabuteau H (2022) Efficacy and safety of AXS-05 (Dextromethorphan-Bupropion) in patients with major depressive disorder: a phase 3 randomized clinical trial (GEMINI). J Clin Psychiatry 83:21m14345. https://doi.org/10.4088/JCP.21m14345

Article  PubMed  Google Scholar 

De Martin S, Gabbia D, Folli F, Bifari F, Fiorina P, Ferri N, Stahl S, Inturrisi CE, Pappagallo M, Traversa S, Manfredi PL (2021) REL-1017 (Esmethadone) increases circulating BDNF levels in healthy subjects of a phase 1 clinical study. Front Pharmacol 12:671859. https://doi.org/10.3389/fphar.2021.671859

Article  CAS  PubMed  PubMed Central  Google Scholar 

Fava M, Stahl S, Pani L, De Martin S, Pappagallo M, Guidetti C, Alimonti A, Bettini E, Mangano RM, Wessel T, de Somer M, Caron J, Vitolo OV, DiGuglielmo GR, Gilbert A, Mehta H, Kearney M, Mattarei A, Gentilucci M, Folli F, Traversa S, Inturrisi CE, Manfredi PL (2022) REL-1017 (Esmethadone) as adjunctive treatment in patients with major depressive disorder: a phase 2a randomized double-blind trial. Am J Psychiatry 179:122–131. https://doi.org/10.1176/appi.ajp.2021.21020197

Article  PubMed  Google Scholar 

Guidetti C, Fava M, Pani L, Pappagallo M, Serra G, DeMartin S, Mattarei A, Manfredi PL (2022) A phase 2a double-blind randomized trial of REL-1017 (Esmethadone) in patients with MDD: analysis of subscales from the symptoms of depression questionnaire. CNS Spectr 27:235. https://doi.org/10.1017/S1092852922000359

Article  Google Scholar 

Gorman AL, Elliott KJ, Inturrisi CE (1997) The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci Lett 223:5–8. https://doi.org/10.1016/s0304-3940(97)13391-2

Article  CAS  PubMed  Google Scholar 

Bettini E, Stahl SM, De Martin S, Mattarei A, Sgrignani J, Carignani C, Nola S, Locatelli P, Pappagallo M, Inturrisi C, Bifari F, Cavalli A, Alimonti A, Pani L, Fava M, Traversa S, Folli F, Manfredi PL (2022) Pharmacological comparative characterization of REL-1017 (Esmethadone-HCl) and other NMDAR channel blockers in human heterodimeric N-methyl-D-aspartate receptors. Pharmaceuticals (Basel) 15:997. https://doi.org/10.3390/ph15080997

Article  CAS  PubMed  Google Scholar 

Kotermanski SE, Johnson JW (2009) Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer’s drug memantine. J Neurosci 29:2774–2779. https://doi.org/10.1523/JNEUROSCI.3703-08.2009

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bernstein G, Davis K, Mills C, Wang L, McDonnell M, Oldenhof J, Inturrisi C, Manfredi PL, Vitolo OV (2019) Characterization of the safety and pharmacokinetic profile of D-methadone, a novel N-methyl-D-aspartate receptor antagonist in healthy, opioid-naive subjects: results of two phase 1 studies. J Clin Psychopharmacol 39:226–237. https://doi.org/10.1097/JCP.0000000000001035

Article  CAS  PubMed  Google Scholar 

Zhang JC, Yao W, Hashimoto K (2022) Arketamine, a new rapid-acting antidepressant: a historical review and future directions. Neuropharmacology 218:109219. https://doi.org/10.1016/j.neuropharm.2022.109219

Article  CAS  PubMed  Google Scholar 

Sanacora G, Smith MA, Pathak S, Su HL, Boeijinga PH, McCarthy DJ, Quirk MC (2014) Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects. Mol Psychiatry 19:978–985. https://doi.org/10.1038/mp.2013.130

Article  CAS  PubMed  Google Scholar 

Bettini E, De Martin S, Mattarei A, Pappagallo M, Stahl SM, Bifari F, Inturrisi CE, Folli F, Traversa S, Manfredi PL (2022) The N-methyl-D-aspartate receptor blocker REL-1017 (Esmethadone) reduces calcium influx induced by glutamate, quinolinic acid, and gentamicin. Pharmaceuticals (Basel) 15:882.