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CNS & Neurological Disorders - Drug Targets


ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Mini-Review Article

Importance of Exploring N-Methyl-D-Aspartate (NMDA) as a Future Perspective Target in Depression

Author(s): Nirav Yogesh Bhatia, Hemen Sanjay Ved, Pravin Popatrao Kale and Gaurav Mahesh Doshi*

Volume 21, Issue 10, 2022

Published on: 10 May, 2022

Page: [1004 - 1016] Pages: 13

DOI: 10.2174/1871527321666220329141639

Price: $65


Major depressive disorder (MDD) is a serious and complex mental illness. Currently, many antidepressants are available in the market for the treatment of MDD. However, these agents are associated with side effects, which restricts their use. This warrants the development of advanced antidepressive medications with a novel mechanism of action or novel targets and with minimal adverse effects. The traditional neurobiological hypothesis of depression, the monoamine hypothesis, is unable to properly explain all the aspects of depressive conditions. In this review, we discuss novel approaches that could be used for the treatment of depression, including glutamatergic and serotonergic system modulation. The pathogenesis of depression is greatly affected by glutamatergic neurotransmission dysfunction. Previous investigations have shown that ketamine, an N-methyl-D-aspartate receptor antagonist, exerts fast and long-lasting antidepressant effects. Several glutamatergic modulators, such as esketamine, sarcosine, and others, have also shown potential antidepressant action in animal as well as clinical studies. Lastly, drugs that alter neurotransmission by NMDA receptors could open up new avenues for more effective treatment of depression. Besides, understanding the underlying mechanisms will aid in the development of novel and fast-acting antidepressant drugs in the future.

Keywords: Depression, NMDA receptors, glutamate, serotonin, ketamine, esketamine.

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Kessler RC, Angermeyer M, Anthony JC, et al. Lifetime prevalence and age-of-onset distributions of mental disorders in the World Health Organization’s world mental health survey initiative. World Psychiatry 2007; 6(3): 168-76.
[PMID: 18188442]
Katon WJ. Clinical and health services relationships between major depression, depressive symptoms, and general medical illness. Biol Psychiatry 2003; 54(3): 216-26.
Kumar A. Current advances in the treatment of major depression: Shift towards receptor specific drugs. In: Woolfolk R, Allen L, Eds. Mental Disorders - Theoretical and Empirical Perspectives. London: IntechOpen 2013.
Inskip HM, Harris EC, Barraclough B. Lifetime risk of suicide for affective disorder, alcoholism and schizophrenia. Br J Psychiatry 1998; 172: 35-7.
[] [PMID: 9534829]
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(11): 1905-17.
[] [PMID: 17074942]
Blier P, Ward HE, Tremblay P, Laberge L, Hébert C, Bergeron R. Combination of antidepressant medications from treatment initiation for major depressive disorder: A double-blind randomized study. Am J Psychiatry 2010; 167(3): 281-8.
[] [PMID: 20008946]
Cuijpers P, van Straten A, Warmerdam L, Andersson G. Psychotherapy versus the combination of psychotherapy and pharmacotherapy in the treatment of depression: A meta-analysis. Depress Anxiety 2009; 26(3): 279-88.
[] [PMID: 19031487]
Alpert J. Prevention of relapse and recurrence in depression: The role of long-term pharmacotherapy and psychotherapy. J Clin Psychiatry 2003; 64(Suppl. 15): 13-7.
Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62(6): 593-602.
[] [PMID: 15939837]
Murray CL, Lopez AD. Burden of disease a comprehensive assessment of mortality and disability from diseases, injuries, and risk fac-tors in 1990 and projected to 2020 Library of Congress Cataloging-In-Publication (CIP) Data applied for. Harvard University Press 1996.
Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 2003; 53: 649-59.
Keller MB, Lavori PW, Mueller TI, et al. Time to recovery, chronicity, and levels of psychopathology in major depression. A 5-year prospective follow-up of 431 subjects. Arch Gen Psychiatry 1992; 49(10): 809-16.
[] [PMID: 1417434]
Fink M. Convulsive therapy: A review of the first 55 years. J Affect Disord 2001; 63(1-3): 1-15.
[] [PMID: 11246075]
Nierenberg AA, DeCecco LM. Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: A focus on treatment-resistant depression. J Clin Psychiatry 2001; 62(Suppl. 16): 5-9.
Healy D, Savage M. Reserpine exhumed. Br J Psychiatry 1998; 172: 376-8.
Anderson IM, Parry-Billings M, Newsholme EA, Poortmans JR, Cowen PJ. Decreased plasma tryptophan concentration in major depres-sion: Relationship to melancholia and weight loss. J Affect Disord 1990; 20(3): 185-91.
[] [PMID: 2148339]
Bus BAA, Molendijk ML. The neurotrophic hypothesis of depression. Tijdschr Psychiatr 2016; 58(3): 215-22.
[PMID: 26979853]
Duval F, Mokrani MC, Ortiz JA, Schulz P, Champeval C, Macher JP. Neuroendocrine predictors of the evolution of depression. Dialogues Clin Neurosci 2005; 7(3): 273-82.
[] [PMID: 16156385]
Cai M, Wang H, Zhang X. Potential anti-depressive treatment maneuvers from bench to bedside. Adv Exp Med Biol 2019; 1180: 277-95.
Martinowich K, Manji H, Lu B. New insights into BDNF function in depression and anxiety. Nat Neurosci 2007; 10(9): 1089-93.
[] [PMID: 17726474]
Skolnick P, Popik P, Trullas R. Glutamate-based antidepressants: 20 years on. Trends Pharmacol Sci 2009; 30(11): 563-9.
[] [PMID: 19837463]
Valentine GW, Sanacora G. Targeting glial physiology and glutamate cycling in the treatment of depression. Biochem Pharmacol 2009; 78(5): 431-9.
Musazzi L, Treccani G, Mallei A, Popoli M. The action of antidepressants on the glutamate system: Regulation of glutamate release and glutamate receptors. Biol Psychiatry 2013; 73(12): 1180-8.
[] [PMID: 23273725]
Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000; 47(4): 351-4.
[] [PMID: 10686270]
Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depres-sion. Arch Gen Psychiatry 2006; 63(8): 856-64.
[] [PMID: 16894061]
Valentine GW, Mason GF, Gomez R, et al. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS. Psychiatry Res 2011; 191(2): 122-7.
[] [PMID: 21232924]
Niciu MJ, Henter ID, Luckenbaugh DA, Zarate CA, Charney DS. Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: Ketamine and other compounds. Annu Rev Pharmacol Toxicol 2014; 54: 119-39.
Abdallah CG, Averill LA, Krystal JH. Ketamine as a promising prototype for a new generation of rapid-acting antidepressants. Ann N Y Acad Sci 2015; 1344(1): 66-77.
[] [PMID: 25727103]
Carr DB, Goudas LC, Denman WT, et al. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: A randomized, double-blind, placebo-controlled, crossover study. Pain 2004; 108(1-2): 17-27.
[] [PMID: 15109503]
Lapidus KAB, Levitch CF, Perez AM, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry 2014; 76(12): 970-6.
[] [PMID: 24821196]
Ibrahim L, Diazgranados N, Franco-Chaves J, et al. Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs. add-on riluzole: Results from a 4-week, double-blind, placebo-controlled study. Neuropsychopharmacology 2012; 37(6): 1526-33.
[] [PMID: 22298121]
McMullen EP, Lee Y, Lipsitz O, et al. Strategies to prolong ketamine’s efficacy in adults with treatment-resistant depression. Adv Thera-py Adis 2021; 38: 2795-820.
Conley AA, Norwood AEQ, Hatvany TC, Griffith JD, Barber KE. Efficacy of ketamine for major depressive episodes at 2, 4, and 6-weeks post-treatment: A meta-analysis. Psychopharmacology (Berl) 2021; 238(7): 1737-52.
[] [PMID: 33787963]
Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry 2013; 74(4): 250-6.
[] [PMID: 22840761]
Liebrenz M, Stohler R, Borgeat A. Repeated intravenous ketamine therapy in a patient with treatment-resistant major depression. World J Biol Psychiatry 2009; 10(4 Pt 2): 640-3.
[] [PMID: 17853274]
aan het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry 2010; 67(2): 139-45.
Niciu MJ, Ionescu DF, Richards EM, Zarate CA Jr. Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder. J Neural Transm (Vienna) 2014; 121(8): 907-24.
[] [PMID: 24318540]
Duman RS, Li N, Liu RJ, Duric V, Aghajanian G. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuro-pharmacology Neuropharmacology 2012; 62(1): 35-41.
Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010; 329(5994): 959-64.
Zhou W, Wang N, Yang C, Li XM, Zhou ZQ, Yang JJ. Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur Psychiatry 2014; 29(7): 419-23.
[] [PMID: 24321772]
Autry AE, Adachi M, Nosyreva E, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 2011; 475(7354): 91-5.
[] [PMID: 21677641]
Chen G, Huang LD, Jiang YM, Manji HK. The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. J Neurochem 1999; 72(3): 1327-30.
[] [PMID: 10037507]
Beurel E, Song L, Jope RS. Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol Psychiatry 2011; 16: 1068-70.
Perrine SA, Ghoddoussi F, Michaels MS, Sheikh IS, McKelvey G, Galloway MP. Ketamine reverses stress-induced depression-like be-havior and increased GABA levels in the anterior cingulate: An 11.7 T 1H-MRS study in rats. Prog Neuropsychopharmacol Biol Psychiatry 2014; 51: 9-15.
[] [PMID: 24246571]
Lener MS, Niciu MJ, Ballard ED, et al. Glutamate and gamma-aminobutyric acid systems in the pathophysiology of major depression and antidepressant response to ketamine. Biol Psychiatry 2017; 81: 886-97.
Andrade C. Ketamine for depression, 3: Does chirality matter? J Clin Psychiatry 2017; 78(6): e674-7.
[] [PMID: 28682536]
Muller J, Pentyala S, Dilger J, Pentyala S. Ketamine enantiomers in the rapid and sustained antidepressant effects. Ther Adv Psychopharmacol 2016; 6(3): 185-92.
[] [PMID: 27354907]
Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI. Ketamine: A review of clinical pharmacokinetics and pharmacodynamics in anes-thesia and pain therapy. Clin Pharmacokinet 2016; 55(9): 1059-77.
Pfenninger EG, Durieux ME, Himmelseher S. Cognitive impairment after small-dose ketamine isomers in comparison to equianalgesic racemic ketamine in human volunteers. Anesthesiology 2002; 96(2): 357-66.
[] [PMID: 11818769]
Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry 2018; 75(2): 139-48.
[] [PMID: 29282469]
Bozymski KM, Crouse EL, Titus-Lay EN, Ott CA, Nofziger JL, Kirkwood CK. Esketamine: A novel option for treatment-resistant de-pression. Ann Pharmacother 2020; 54(6): 567-76.
Swainson J, Thomas RK, Archer S, et al. Esketamine for treatment resistant depression. Expert Rev Neurother 2019; 19(10): 899-911.
[] [PMID: 31282772]
Turner EH. Esketamine for treatment-resistant depression: Seven concerns about efficacy and FDA approval. Lancet Psychiatry 2019; 6(12): 977-9.
Horowitz MA, Moncrieff J. Are we repeating mistakes of the past? A review of the evidence for esketamine. Br J Psychiatry 2021; 219(5): 614-7.
Wei Y, Chang L, Hashimoto K. Molecular mechanisms underlying the antidepressant actions of arketamine: Beyond the NMDA receptor. Mol Psychiatry 2021; 2021: 1-15.
[] [PMID: 33963284]
Yang C, Shirayama Y, Zhang JC, et al. R-ketamine: A rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry 2015; 5(9): e632.
[] [PMID: 26327690]
Zanos P, Moaddel R, Morris PJ, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 2016; 533(7604): 481-6.
[] [PMID: 27144355]
Zhang J-C, Li S-X, Hashimoto K R. (−)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)- ketamine. Pharmacol Biochem Behav 2014; 116: 137-41.
Leal GC, Bandeira ID, Correia-Melo FS, et al. Intravenous arketamine for treatment-resistant depression: Open-label pilot study. Eur Arch Psychiatry Clin Neurosci 2021; 271(3): 577-82.
[] [PMID: 32078034]
Hashimoto K. Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine. Biochem Pharmacol 2020; 177: 1113935.
Menniti FS, Pagnozzi MJ, Butler P, Chenard BL, Jaw-Tsai SS, Frost White W. CP-101,606, an NR2B subunit selective NMDA receptor antagonist, inhibits NMDA and injury induced c-fos expression and cortical spreading depression in rodents. Neuropharmacology 2000; 39(7): 1147-55.
[] [PMID: 10760358]
Louderback KM, Wills TA, Muglia LJ, Winder DG. Knockdown of BNST GluN2B-containing NMDA receptors mimics the actions of ketamine on novelty-induced hypophagia. Transl Psychiatry 2013; 3(12): e331.
[] [PMID: 24301649]
Miller OH, Yang L, Wang CC, et al. GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. eLife 2014; 3(3): e03581.
[] [PMID: 25340958]
Graef JD, Newberry K, Newton A, et al. Effect of acute NR2B antagonist treatment on long-term potentiation in the rat hippocampus. Brain Res 2015; 1609(1): 31-9.
[] [PMID: 25796435]
Preskorn SH, Baker B, Kolluri S, Menniti FS, Krams M, Landen JW. An innovative design to establish proof of concept of the antide-pressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol 2008; 28(6): 631-7.
[] [PMID: 19011431]
Hillhouse TM, Porter JH. A brief history of the development of antidepressant drugs: From monoamines to glutamate. Exp Clin Psychopharmacol 2015; 23(1): 1-21.
[] [PMID: 25643025]
Ibrahim L, Diaz Granados N, Jolkovsky L, et al. A Randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder. J Clin Psychopharmacol 2012; 32(4): 551-7.
[] [PMID: 22722512]
Wang M, Yang Y, Dong Z, Cao J, Xu L. NR2B-containing N-methyl-D-aspartate subtype glutamate receptors regulate the acute stress effect on hippocampal long-term potentiation/long-term depression in vivo. Neuroreport 2006; 17(12): 1343-6.
[] [PMID: 16951582]
Kochlamazashvili G, Bukalo O, Senkov O, et al. Restoration of synaptic plasticity and learning in young and aged NCAM-deficient mice by enhancing neurotransmission mediated by GluN2A-containing NMDA receptors. J Neurosci 2012; 32(7): 2263-75.
[] [PMID: 22396402]
Rouaud E, Billard JM. D-cycloserine facilitates synaptic plasticity but impairs glutamatergic neurotransmission in rat hippocampal slices. Br J Pharmacol 2003; 140(6): 1051-6.
[] [PMID: 14530208]
Donzis EJ, Thompson LT. D-cycloserine enhances both intrinsic excitability of CA1 hippocampal neurons and expression of activity-regulated cytoskeletal (Arc) protein. Neurosci Lett 2014; 571: 50-4.
[] [PMID: 24793770]
Heresco-Levy U, Javitt DC, Gelfin Y, et al. Controlled trial of D-cycloserine adjuvant therapy for treatment-resistant major depressive disorder. J Affect Disord 2006; 93(1-3): 239-43.
[] [PMID: 16677714]
Heresco-Levy U, Gelfin G, Bloch B, et al. A randomized add-on trial of high-dose D-cycloserine for treatment-resistant depression. Int J Neuropsychopharmacol 2013; 16(3): 501-6.
[] [PMID: 23174090]
Burgdorf J, Zhang XL, Nicholson KL, et al. GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology 2013; 38(5): 729-42.
[] [PMID: 23303054]
Burgdorf J, Zhang XL, Weiss C, et al. The long-lasting antidepressant effects of rapastinel (GLYX-13) are associated with a metaplastici-ty process in the medial prefrontal cortex and hippocampus. Neuroscience 2015; 308: 202-11.
[] [PMID: 26343295]
Huang CC, Wei IH, Huang CL, et al. Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression. Biol Psychiatry 2013; 74(10): 734-41.
[] [PMID: 23562005]
Chen KT, Wu CH, Tsai MH, et al. Antidepressant-like effects of long-term sarcosine treatment in rats with or without chronic unpredict-able stress. Behav Brain Res 2017; 316: 1-10.
[] [PMID: 27555541]
Chen KT, Tsai MH, Wu CH, Jou MJ, Wei IH, Huang CC. AMPA receptor–mTOR activation is required for the antidepressant-like effects of sarcosine during the forced swim test in rats: Insertion of AMPA receptor may play a role. Front Behav Neurosci 2015; 9: 162.
[] [PMID: 26150775]
Mullard A. Deuterated drugs draw heavier backing. Nat Rev Drug Discov 2016; 15: 219-21.
Machado-Vieira R, Salvadore G, Diazgranados N, Zarate CA Jr. Ketamine and the next generation of antidepressants with a rapid onset of action. Pharmacol Ther 2009; 123(2): 143-50.
[] [PMID: 19397926]
Segmiller F, Rüther T, Linhardt A, et al. Repeated S-ketamine infusions in therapy resistant depression: A case series. J Clin Pharmacol 2013; 53(9): 996-8.
[] [PMID: 23893490]
O’Toole E, Doucet MV, Sherwin E, Harkin A. Novel targets in the glutamate and nitric oxide neurotransmitter systems for the treatment of depression. Syst Neurosci Depress 2016; pp. 81-113.
Vollenweider FX, Kometer M. The neurobiology of psychedelic drugs: Implications for the treatment of mood disorders. Nat Rev Neurosci 2010; 11(9): 642-51.
Carhart-Harris RL, Kaelen M, Bolstridge M, et al. The paradoxical psychological effects of lysergic acid diethylamide (LSD). Psychol Med 2016; 46(7): 1379-90.
[] [PMID: 26847689]
De Gregorio D, Enns JP, Nuñez NA, Posa L, Gobbi G. d-Lysergic acid diethylamide, psilocybin, and other classic hallucinogens: Mechanism of action and potential therapeutic applications in mood disorders. Prog Brain Res 2018; 242: 69-96.
[] [PMID: 30471683]
Haddjeri N, Blier P, de Montigny C. Long-term antidepressant treatments result in a tonic activation of forebrain 5-HT1A receptors. J Neurosci 1998; 18(23): 10150-6.
[] [PMID: 9822768]
Nichols DE. Psychedelics. Pharmacol Rev 2016; 68(2): 264-355.
[] [PMID: 26841800]
Bouso JC, Ona G, Dos Santos RG, Hallak JEC. Psychedelic medicines in major depression: Progress and future challenges. Adv Exp Med Biol 2021; 1305: 515-33.
[] [PMID: 33834416]
Estrella-Parra EA, Almanza-Pérez JC, Alarcón-Aguilar FJ. Ayahuasca: Uses, phytochemical and biological activities. Nat Prod Bioprospect 2019; 9(4): 251-65.
[] [PMID: 31134518]
Callaway JC, Airaksinen MM, McKenna DJ, Brito GS, Grob CS. Platelet serotonin uptake sites increased in drinkers of ayahuasca. Psychopharmacology (Berl) 1994; 116(3): 385-7.
[] [PMID: 7892432]
Gresch PJ, Smith RL, Barrett RJ, Sanders-Bush E. Behavioral tolerance to lysergic acid diethylamide is associated with reduced seroto-nin-2A receptor signaling in rat cortex. Neuropsychopharmacology 2005; 30(9): 1693-702.
[] [PMID: 15756304]
Inserra A, De Gregorio D, Gobbi G. Psychedelics in psychiatry: Neuroplastic, immunomodulatory, and neurotransmitter mechanisms. Pharmacol Rev 2021; 73(1): 202-77.
[] [PMID: 33328244]
Galvão-Coelho NL, Marx W, Gonzalez M, et al. Classic serotonergic psychedelics for mood and depressive symptoms: A meta-analysis of mood disorder patients and healthy participants. Psychopharmacology 2021; 238: 341-54.
Dos Santos RG, Osório FL, Crippa JAS, Riba J, Zuardi AW, Hallak JEC. Antidepressive, anxiolytic, and antiaddictive effects of ayahuas-ca, psilocybin and lysergic acid diethylamide (LSD): A systematic review of clinical trials published in the last 25 years. Ther Adv Psychopharmacol 2016; 6(3): 193-213.
[] [PMID: 27354908]
Bershad AK, Schepers ST, Bremmer MP, Lee R, de Wit H. Acute subjective and behavioral effects of microdoses of lysergic acid di-ethylamide in healthy human volunteers. Biol Psychiatry 2019; 86(10): 792-800.
[] [PMID: 31331617]
Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin with psychological support for treatment-resistant depression: An open-label feasibility study. Lancet Psychiatry 2016; 3(7): 619-27.
[] [PMID: 27210031]
Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol 2016; 30(12): 1181-97.
[] [PMID: 27909165]
Osório Fde L, Sanches RF, Macedo LR, et al. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: A preliminary report. Rev Bras Psiquiatr 2015; 37(1): 13-20.
[] [PMID: 25806551]
Dos Santos RG, Balthazar FM, Bouso JC, Hallak JEC. The current state of research on ayahuasca: A systematic review of human studies assessing psychiatric symptoms, neuropsychological functioning, and neuroimaging. J Psychopharmacol 2016; 30(12): 1230-47.
[] [PMID: 27287824]
Carhart-Harris RL, Goodwin GM. The therapeutic potential of psychedelic drugs: Past, present, and future. Neuropsychopharmacology 2017; 42(11): 2105-13.
[] [PMID: 28443617]
Tiligada E, Kyriakidis K, Chazot PL, Passani MB. Histamine pharmacology and new CNS drug targets. CNS Neurosci Ther 2011; 17(6): 620-8.
[] [PMID: 22070192]
Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: New insights from stress and rapid-acting anti-depressants. Nat Med 2016; 22(3): 238-49.
Fossati P, Radtchenko A, Boyer P. Neuroplasticity: From MRI to depressive symptoms. Eur Neuropsychopharmacol 2004; 14(Suppl. 5): S503-10.
Pittenger C, Duman RS. Stress, depression, and neuroplasticity: A convergence of mechanisms. Neuropsychopharmacol 2007; 33(1): 88-109.
Player MJ, Taylor JL, Weickert CS, et al. Neuroplasticity in depressed individuals compared with healthy controls. Neuropsychopharmacology 2013; 38(11): 2101-8.
[] [PMID: 23676792]
Payne NA, Prudic J. Electroconvulsive therapy: Part I. A perspective on the evolution and current practice of ECT. J Psychiatr Pract 2009; 15(5): 346-68.
[] [PMID: 19820553]
Avery D, Winokur G. The efficacy of electroconvulsive therapy and antidepressants in depression. Biol Psychiatry 1977; 12(4): 507-23.
[PMID: 889984]
Sackeim HA, Prudic J, Devanand DP, et al. The benefits and costs of changing treatment technique in electroconvulsive therapy due to insufficient improvement of a major depressive episode. Brain Stimul 2020; 13(5): 1284-95.
[] [PMID: 32585354]
Holtzheimer PE III, Nemeroff CB. Advances in the treatment of depression. NeuroRx 2006; 3(1): 42-56.
[] [PMID: 16490412]
Avery D, Winokur G. Suicide, attempted suicide, and relapse rates in depression. Arch Gen Psychiatry 1978; 35(6): 749-53.
[] [PMID: 655772]
Dong J, Min S, Wei K, Li P, Cao J, Li Y. Effects of electroconvulsive therapy and propofol on spatial memory and glutamatergic system in hippocampus of depressed rats. J ECT 2010; 26(2): 126-30.
[] [PMID: 20514696]
Kranaster L, Kammerer-Ciernioch J, Hoyer C, Sartorius A. Clinically favourable effects of ketamine as an anaesthetic for electroconvul-sive therapy: A retrospective study. Eur Arch Psychiatry Clin Neurosci 2011; 261(8): 575-82.
[] [PMID: 21400226]
Sartorius A, Beuschlein J, Remennik D, et al. Empirical ratio of the combined use of S-ketamine and propofol in electroconvulsive ther-apy and its impact on seizure quality. Eur Arch Psychiatry Clin Neurosci 2021; 271(3): 457-63.
[] [PMID: 32699969]
Pagnin D, Queiroz V. de, Pini S, Cassano GB. Efficacy of ECT in depression: A meta-analytic review. Focus 2008; 6(1): 155-62.
Hopman HJ, Choy HY, Ho WS, Lu H, Wong WHO, Chan SMS. The effects of repetitive transcranial magnetic stimulation antidepressant response on cold cognition: A single-arm prospective longitudinal study. Neuropsychiatr Dis Treat 2021; 17: 1647-58.
[] [PMID: 34079262]
Connolly KR, Helmer A, Cristancho MA, Cristancho P, O’Reardon JP. Effectiveness of transcranial magnetic stimulation in clinical prac-tice post-FDA approval in the United States: Results observed with the first 100 consecutive cases of depression at an academic medical center. J Clin Psychiatry 2012; 73(4): e567-73.
[] [PMID: 22579164]
Kim DR, Pesiridou A, O’Reardon JP. Transcranial magnetic stimulation in the treatment of psychiatric disorders. Curr Psychiatry Rep 2009; 11(6): 447-52.
[] [PMID: 19909666]
George MS, Taylor JJ, Short EB. The expanding evidence base for rTMS treatment of depression. Curr Opin Psychiatry 2013; 26: 13-8.
Ueyama E, Ukai S, Ogawa A, et al. Chronic repetitive transcranial magnetic stimulation increases hippocampal neurogenesis in rats. Psychiatry Clin Neurosci 2011; 65(1): 77-81.
[] [PMID: 21265939]
Furtado CP, Hoy KE, Maller JJ, Savage G, Daskalakis ZJ, Fitzgerald PB. An investigation of medial temporal lobe changes and cognition following antidepressant response: A prospective rTMS study. Brain Stimul 2013; 6(3): 346-54.
[] [PMID: 22784443]
Brunelin J, Fecteau S. Can the effects of noninvasive brain stimulation alleviating neuropsychiatric symptoms result from a common beneficial regulation of the hypothalamic-pituitary-adrenal axis? Brain Stimul 2015; 8(2): 173-6.
[] [PMID: 25556003]
Slotema CW, Blom JD, Hoek HW, Sommer IEC. Should we expand the toolbox of psychiatric treatment methods to include repetitive Transcranial Magnetic Stimulation (rTMS)? A meta-analysis of the efficacy of rTMS in psychiatric disorders. J Clin Psychiatry 2010; 71(7): 873-84.
[] [PMID: 20361902]
Rush AJ, George MS, Sackeim HA, et al. Vagus Nerve Stimulation (VNS) for treatment-resistant depressions: A multicenter study. Biol Psychiatry 2000; 47(4): 276-86.
[] [PMID: 10686262]
Aaronson ST, Sears P, Ruvuna F, et al. A 5-year observational study of patients with treatment-resistant depression treated with vagus nerve stimulation or treatment as usual: Comparison of response, remission, and suicidality. Am J Psychiatry 2017; 174(7): 640-8.
[] [PMID: 28359201]
Brunoni AR, Sampaio B, Moffa AH, et al. The Escitalopram versus Electric Current Therapy for Treating Depression Clinical Study (ELECT-TDCS): Rationale and study design of a non-inferiority, triple-arm, placebo-controlled clinical trial. Sao Paulo Med J 2015; 133(3): 252-63.
[] [PMID: 26176930]
Meron D, Hedger N, Garner M, Baldwin DS. Transcranial direct current stimulation (tDCS) in the treatment of depression: Systematic review and meta-analysis of efficacy and tolerability. Neurosci Biobehav Rev 2015; 46-62.
Chaimowitz G, Weerasekera P, Ravitz P. Psychotherapy in psychiatry. Can J Psychiatry 2021; 66(11): 64.
Parikh SV, Segal ZV, Grigoriadis S, Ravindran AV, Kennedy SH, Lam RW. Canadian network for mood and anxiety treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. II. Psychotherapy alone or in combination with antidepressant medication. J Affect Disord 2009; 117(Suppl. 1): S15-25.
Effectiveness of ketamine for depression and suicidal ideation in the emergency department - Full text view. ClinicalTrials 2020. Available from:
Grunebaum MF, Galfalvy HC, Choo TH, et al. Ketamine for rapid reduction of suicidal thoughts in major depression: A midazolam-controlled randomized clinical trial. Am J Psychiatry 2018; 175(4): 327-35.
[] [PMID: 29202655]
Hu YD, Xiang YT, Fang JX, et al. Single i.v. ketamine augmentation of newly initiated escitalopram for major depression: Results from a randomized, placebo-controlled 4-week study. Psychol Med 2016; 46(3): 623-35.
[] [PMID: 26478208]
Study to evaluate the efficacy, safety, and tolerability of fixed doses of intranasal esketamine plus an oral antidepressant in adult participants with treatment-resistant depression - Full text view. ClinicalTrialsgov 2016. Available from:
A study to evaluate the efficacy, safety, and tolerability of flexible doses of intranasal esketamine plus an oral antidepressant in adult participants with treatment-resistant depression - Full text view. ClinicalTrialsgov 2016. Available from:
A study to evaluate the efficacy, safety, and tolerability of intranasal esketamine plus an oral antidepressant in elderly participants with treatment-resistant depression - Full text view. ClinicalTrialsgov 2016. Available from:
A study of intranasal esketamine plus an oral antidepressant for relapse prevention in adult participants with treatment-resistant depression - Full text view. ClinicalTrialsgov 2016. Available from:
A long-term, safety and efficacy study of intranasal esketamine in treatment-resistant depression - Full text view. ClinicalTrialsgov Available from:
Zarate CA Jr, Mathews D, Ibrahim L, et al. A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression. Biol Psychiatry 2013; 74(4): 257-64.
[] [PMID: 23206319]
D-cycloserine for major depressive disorder - Full text view. ClinicalTrialsgov 2016. Available from:
Clinical trial on treatment resistant depression: Ketamine, Dcycloserine, placebo - clinical trials registry - ICH GCP.
Study of rapastinel as monotherapy in patients with MDD - Full text view. ClinicalTrialsgov Available from:
Study of rapastinel as monotherapy in patients with major depressive disorder (MDD) Full text view. ClinicalTrialsgov 2016. Available from:
Garay RP, Zarate CA, Charpeaud T, et al. Investigational drugs in recent clinical trials for treatment-resistant depression. Expert Rev Neurother 2017; 17(6): 593-609.
Preskorn S, Macaluso M, Mehra DO, Zammit G, Moskal JR, Burch RM. GLYX-13 Clinical Study Group. Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previ-ous antidepressant agent. J Psychiatr Pract 2015; 21(2): 140-9.
[] [PMID: 25782764]
N-methylglycine (Sarcosine) Treatment for Depression - Full Text View. ClinicalTrialsgov 2016. Available from:
A study to assess the efficacy and safety of AXS-05 in subjects with treatment resistant major depressive disorder - Full text view. ClinicalTrialsgov 2016. Available from:
Davis AK, Barrett FS, May DG, et al. Effects of psilocybin-assisted therapy on major depressive disorder: A randomized clinical trial. JAMA Psychiatry 2021; 78(5): 481-9.
[] [PMID: 33146667]
Carhart-Harris RL, Bolstridge M, Day CMJ, et al. Psilocybin with psychological support for treatment-resistant depression: Six-month follow-up. Psychopharmacology (Berl) 2018; 235(2): 399-408.
[] [PMID: 29119217]
Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of psilocybin versus escitalopram for depression. 2021; 384(15): 1402-1.
Psilocybin vs. Escitalopram for major depressive disorder: Comparative mechanisms - Full text view. ClinicalTrialsgov 2016. Available from:
Palhano-Fontes F, Barreto D, Onias H, et al. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: A randomized placebo-controlled trial. Psychol Med 2019; 49(4): 655-63.
[] [PMID: 29903051]
Antidepressant effects of ayahuasca: A randomized placebo controlled trial in treatment resistant depression - Full text view. ClinicalTrialsgov 2016. Available from:
Sarris J, Perkins D, Cribb L, et al. Ayahuasca use and reported effects on depression and anxiety symptoms: An international cross-sectional study of 11,912 consumers. J Affect Disord Reports 2021; 4: 100098.

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