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Review Article | Open Access

Research progress of non-monoamine antidepressants

Huan Zhang§Bo Wang§Xiaohua Cao( )
Key Laboratory of Brain Functional Genomics, East China Normal University, Shanghai 200062, China

§ Huan Zhang and Bo Wang contributed equally to this work.

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Graphical Abstract


Major depressive disorder (MDD) is a recurring mental illness that has brought severe physical and psychological burdens to people around the world and caused heavy medical and economic burdens on society. For many years, the monoamine hypothesis based on the first- and second-generation antidepressants have been developed and put into clinical use, but the traditional monoamine antidepressants have a series of problems, such as poor targeting, strong side effects, and slow onset. The emergence of non-monoamine antidepressants such as ketamine, scopolamine, and brexanolone has injected new impetus into the development of long-silent antidepressants. They have the characteristics of fast onset, low toxicity, fewer side effects, and a better response rate to treatment-resistant depression (TRD). This review will discuss the characteristics, mechanisms, advantages, and remaining problems of non-monoamine antidepressants, and provide recommendations for future clinical and scientific research.


Kessler, R. C., Bromet, E. J. The epidemiology of depression across cultures. Annual Review of Public Health, 2013, 34: 119-138.
Otte, C., Gold, S. M., Penninx, B. W., Pariante, C. M., Etkin, A., Fava, M., Mohr, D. C., Schatzberg, A. F. Major depressive disorder. Nature Review Disease Primers, 2016, 2: 16065.
Kessler, R. C., Gruber, M., Hettema, J. M., Hwang, I., Sampson, N., Yonkers, K. A. Co-morbid major depression and generalized anxiety disorders in the National Comorbidity Survey follow-up. Psychological Medicine, 2008, 38(3): 365-374.
Smith, K. Mental health: A world of depression. Nature, 2014, 515(7526): 181.
Kato, T., Kanba, S. Conquering depression. Psychiatry and Clinical Neurosciences, 2015, 69(1): 1-2.
Malhi, G, S., Mann, J. J. Depression. The Lancet, 2018, 392(10161): 2299-2312.
Pletscher, A. The discovery of antidepressants: A winding path. Experientia, 1991, 47(1): 4-8.
Artigas, F. Developments in the field of antidepressants, where do we go now? European Neuropsychopharmacology, 2015, 25(5): 657-670.
White, K. J., Walline, C. C., Barker, E. L. Serotonin transporters: Implications for antidepressant drug development. The AAPS Journal, 2005, 7(2): E421-E433.
Corya, S. A., Williamson, D., Sanger, T. M., Briggs, S. D., Case, M., Tollefson, G. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression. Depression and Anxiety, 2006, 23(6): 364-372.
Gillman, P. K. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. BJA: British Journal of Anaesthesia, 2005, 95(4): 434-441.
Gillman, P. K. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. British Journal of Pharmacology, 2007, 151(6): 737-748.
Li, Y. F. A hypothesis of monoamine (5-HT) - glutamate/GABA long neural circuit: Aiming for fast-onset antidepressant discovery. Pharmacology & Therapeutics, 2020, 208: 107494.
Wang, S. M., Han, C., Bahk, W. M., Lee, S. J., Patkar, A. A., Masand, P. S., Pae, C. U. Addressing the side effects of contemporary antidepressant drugs: A comprehensive review. Chonnam Medical Journal, 2018, 54(2): 101-112.
Feighner, J. P. Mechanism of action of antidepressant medications. The Journal of Clinical Psychiatry, 1999, 60(Suppl 4): 4-11; discussion 12-13.
Peretti, S., Judge, R., Hindmarch, I. Safety and tolerability considerations: tricyclic antidepressants vs. selective serotonin reuptake inhibitors. Acta Psychiatrica Scandinavica, 2000, 403(S403): 17-25.
Wong, D. T., Bymaster, F. P., Engleman, E. A. Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: Twenty years since its first publication. Life Sciences, 1995, 57(5): 411-441.
Perez-Caballero, L., Torres-Sanchez, S., Bravo, L., Mico, J. A., Berrocoso, E. Fluoxetine: a case history of its discovery and preclinical development. Expert Opinion Drug Discovery, 2014, 9(5): 567-578.
Mandrioli, R., Protti, M., Mercolini, L. New-generation, non-SSRI antidepressants: Therapeutic drug monitoring and pharmacological interactions. Part 1: SNRIs, SMSs, SARIs. Current Medicinal Chemistry, 2018, 25(7): 772-792.
Wang, S. M., Han, C., Lee, S. J., Jun, T. Y., Patkar, A. A., Masand, P. S., Pae, C. U. Second generation antipsychotics in the treatment of major depressive disorder: an update. Chonnam Medical Journal, 2016, 52(3): 159-172.
Guaiana, G., Gupta, S., Chiodo, D., Davies, S. J., Haederle, K., Koesters, M. Agomelatine versus other antidepressive agents for major depression. The Cochrane Database of Systematic Reviews, 2013(12): CD008851.
Hansen, R. A., Gartlehner, G., Lohr, K. N., Gaynes, B. N., Carey, T. S. Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder. Annals of Internal Medicine, 2005, 143(6): 415-426.
Pandarakalam, J. P. Challenges of treatment-resistant depression. Psychiatria Danubina, 2018, 30(3): 273-284.
Wang, S. M., Han, C., Lee, S. J., Patkar, A. A., Masand, P. S., Pae, C. U. Vilazodone for the treatment of depression: An update. Chonnam Medical Journal, 2016, 52(2): 91-100.
Jacobsen, P. L., Mahableshwarkar, A. R., Palo, W. A., Chen, Y., Dragheim, M., Clayton, A. H. Treatment-emergent sexual dysfunction in randomized trials of vortioxetine for major depressive disorder or generalized anxiety disorder: A pooled analysis. CNS Spectrums, 2016, 21(5): 367-378.
Zanos, P., Gould, T. D. Mechanisms of ketamine action as an antidepressant. Molecular Psychiatry, 2018, 23(4): 801-811.
Bannerman, D. M., Sprengel, R., Sanderson, D. J., McHugh, S. B., Rawlins, J. N., Monyer, H., Seeburg, P. H. Hippocampal synaptic plasticity, spatial memory and anxiety. Nature Reviews Neuroscience, 2014, 15(3): 181-192.
Baez, M. V., Cercato, M. C., Jerusalinsky, D. A. NMDA receptor subunits change after synaptic plasticity induction and learning and memory acquisition. Neural Plasticity, 2018, 2018: 5093048.
Burgdorf, J., Colechio, E. M., Stanton, P., Panksepp, J. Positive emotional learning induces resilience to depression: A role for NMDA receptor-mediated synaptic plasticity. Current Neuropharmacology, 2017, 15(1): 3-10.
Yang, Y., Cui, Y., Sang, K., Dong, Y., Ni, Z., Ma, S., Hu, H. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature, 2018, 554(7692): 317-322.
Kokane, S. S., Armant, R. J., Bolaños-Guzmán, C. A., Perrotti, L. I. Overlap in the neural circuitry and molecular mechanisms underlying ketamine abuse and its use as an antidepressant. Behavioural Brain Research, 2020, 384: 112548.
Lapidus, K. A., Levitch, C. F., Perez, A. M., Brallier, J. W., Parides, M. K., Soleimani, L., Feder, A., Iosifescu, D. V., Charney, D. S., Murrough, J. W. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biological Psychiatry, 2014, 76(12): 970-976.
Zarate, C. A., Brutsche, N. E., Ibrahim, L., Franco-Chaves, J., Diazgranados, N., Cravchik, A., Selter, J., Marquardt, C. A., Liberty, V., Luckenbaugh, D. A. Replication of ketamine’s antidepressant efficacy in bipolar depression: A randomized controlled add-on trial. Biol Psychiatry, 2012, 71(11): 939-946.
Valentine, G. W., Mason, G. F., Gomez, R., Fasula, M., Watzl, J., Pittman, B., Krystal, J. H., Sanacora, G. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS. Psychiatry Research, 2011, 191(2): 122-127.
Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., Krystal, J. H. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry, 2000, 47(4): 351-354.
Niswender, C. M., Conn, P. J. Metabotropic glutamate receptors: Physiology, pharmacology, and disease. Annual Review of Pharmacology and Toxicology, 2010, 50: 295-322.
Niciu, M. J., Henter, I. D., Luckenbaugh, D. A., Zarate, C. A., Charney, D. S. Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: Ketamine and other compounds. Annu Rev Pharmacol Toxicol, 2014, 54: 119-139.
Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., Charney, D. S., Manji, H. K. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry, 2006, 63(8): 856-864.
Daly, E. J., Singh, J. B., Fedgchin, M., Cooper, K., Lim, P., Shelton, R. C., Thase, M. E., Winokur, A., Van Nueten, L., Manji, H. 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): 139-148.
Singh, J. B., Fedgchin, M., Daly, E., Xi, L., Melman, C., De Bruecker, G., Tadic, A., Sienaert, P., Wiegand, F., Manji, H. et al. Intravenous esketamine in adult treatment-resistant depression: A double-blind, double-randomization, placebo-controlled study. Biological Psychiatry, 2016, 80(6): 424-431.
Canuso, C. M., Singh, J. B., Fedgchin, M., Alphs, L., Lane, R., Lim, P., Pinter, C., Hough, D., Sanacora, G., Manji, H. et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: Results of a double-blind, randomized, placebo-controlled study. The American Journal of Psychiatry, 2018, 175(7): 620-630.
Daly, E. J., Trivedi, M. H., Janik, A., Li, H., Zhang, Y., Li, X., Lane, R., Lim, P., Duca, A. R., Hough, D. 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 Psychiatry, 2019, 76(9): 893-903.
Riad, M., Hithe, C. C. Scopolamine. In: StatPearls. Treasure Island (FL): StatPearls Publishing, 2021.
Gillin, J. C., Sutton, L., Ruiz, C., Darko, D., Golshan, S., Risch, S. C., Janowsky, D. The effects of scopolamine on sleep and mood in depressed patients with a history of alcoholism and a normal comparison group. Biological Psychiatry, 1991, 30(2): 157-169.
Furey, M. L., Drevets, W. C. Antidepressant efficacy of the antimuscarinic drug scopolamine: A randomized, placebo-controlled clinical trial. Archives of General Psychiatry, 2006, 63(10): 1121-1129.
Leader, L. D., O’Connell, M., VandenBerg, A. Brexanolone for postpartum depression: Clinical evidence and practical considerations. Pharmaco-therapy, 2019, 39(11): 1105-1112.
Hutcherson, T. C., Cieri-Hutcherson, N. E., Gosciak, M. F. Brexanolone for postpartum depression. American Journal of Health-System Pharmacy, 2020, 77(5): 336-345.
Powell, J. G., Garland, S., Preston, K., Piszczatoski, C. Brexanolone (zulresso): Finally, an FDA-approved treatment for postpartum depression. The Annals of Pharmacotherapy, 2020, 54(2): 157-163.
Scott, L. J. Brexanolone: first global approval. Drugs, 2019, 79(7): 779-783.
Almeida, F. B., Nin, M. S., Barros, H. M. T. The role of allopregnanolone in depressive-like behaviors: Focus on neurotrophic proteins. Neurobiology of Stress, 2020, 12: 100218.
Zorumski, C. F., Paul, S. M., Covey, D. F., Mennerick, S. Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond. Neurobiology of Stress, 2019, 11: 100196.
Laube, G., Bernstein. H. G. Agmatine: multifunctional arginine metabolite and magic bullet in clinical neuroscience? Biochemical Journal, 2017, 474(15): 2619-2640.
Freitas, A. E., Neis, V. B., Rodrigues, A. L. S. Agmatine, a potential novel therapeutic strategy for depression. European Neuropsychopharmacology, 2016, 26(12): 1885-1899.
Zomkowski, A. D., Hammes, L., Lin, J., Calixto, J. B., Santos, A. R., Rodrigues, A. L. Agmatine produces antidepressant-like effects in two models of depression in mice. Neuroreport, 2002, 13(4): 387-391.
Li, Y. F., Gong, Z. H., Cao, J. B., Wang, H. L., Luo, Z. P., Li, J. Antidepressant-like effect of agmatine and its possible mechanism. European Journal of Pharmacology, 2003, 469(1-3): 81-88.
Freitas, A. E., Bettio, L. E., Neis, V. B., Moretti, M., Ribeiro, C. M., Lopes, M. W., Leal, R. B., Rodrigues, A. L. Sub-chronic agmatine treatment modulates hippocampal neuroplasticity and cell survival signaling pathways in mice. Journal of Psychiatric Research, 2014, 58: 137-146.
Moskal, J. R., Kuo, A. G., Weiss, C., Wood, P. L., Hanson, A. O., Kelso, S., Harris, R. B., Disterhoft, J. F. Glyx-13: A monoclonal antibody-derived peptide that acts as an N-methyl-D-aspartate receptor modulator. Neuropharmacology, 2005, 49(7): 1077-1087.
Burgdorf, J., Zhang, X. L., Weiss, C., Gross, A., Boikess, S. R., Kroes, R. A., Khan, M. A., Burch, R. M., Rex, C. S., Disterhoft, J. F. et al. The long-lasting antidepressant effects of rapastinel (GLYX-13) are associated with a metaplasticity process in the medial prefrontal cortex and hippocampus. Neuroscience, 2015, 308: 202-211.
Burgdorf, J., Zhang, X. L., Weiss, C., Matthews, E., Disterhoft, J. F., Stanton, P. K., Moskal, J. R. The N-methyl-D-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats. Neurobiol Aging, 2011, 32(4): 698-706.
Preskorn, S., Macaluso, M., Mehra, D. O., Zammit, G., Moskal, J. R., Burch, R. M., 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 previous antidepressant agent. Journal of Psychiatric Practice, 2015, 21(2): 140-149.
Kato, T., Duman, R. S. Rapastinel, a novel glutamatergic agent with ketamine-like antidepressant actions: Convergent mechanisms. Pharmacology Biochemistry and Behavior, 2020, 188: 172827.
Kadriu, B., Musazzi, L., Henter, I. D., Graves, M., Popoli, M., Zarate, C. A. Glutamatergic neurotrans-mission: Pathway to developing novel rapid-acting antidepressant treatments. International Journal of Neuropsychopharmacology, 2019, 22(2): 119-135.
Autry, A. E., Adachi, M., Nosyreva, E., Na, E. S., Los, M. F., Cheng, P. F., Kavalali, E. T., Monteggia, L. M. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature, 2011, 475(7354): 91-95.
Li, N., Liu, R. J., Dwyer, J. M., Banasr, M., Lee, B., Son, H., Li, X. Y., Aghajanian, G., Duman, R. S. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry, 2011, 69(8): 754-761.
Li, N., Lee, B., Liu, R. J., Banasr, M., Dwyer, J. M., Iwata, M., Li, X. Y., Aghajanian, G., Duman, R. S. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science, 2010, 329(5994): 959-964.
Homayoun, H., Moghaddam, B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. Journal of Neuroscience, 2007, 27(43): 11496-11500.
Duman, R. S., Li, N., Liu, R. J., Duric, V., Aghajanian, G. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neurophar-macology, 2012, 62(1): 35-41.
Ghosal, S., Bang, E., Yue, W., Hare, B. D., Lepack, A. E., Girgenti, M. J., Duman, R. S. Activity-dependent brain-derived neurotrophic factor release is required for the rapid antidepressant actions of scopolamine. Biological Psychiatry, 2018, 83(1): 29-37.
Phillips, C. Brain-derived neurotrophic factor, depression, and physical activity: Making the neuroplastic connection. Neural Plasticity, 2017, 2017: 7260130.
Liu, R. J., Lee, F. S., Li, X. Y., Bambico, F., Duman, R. S., Aghajanian, G. K. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biological Psychiatry, 2012, 71(11): 996-1005.
Cui, Y., Yang, Y., Ni, Z., Dong, Y., Cai, G., Foncelle, A., Ma, S., Sang, K., Tang, S., Li, Y. et al. Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature, 2018, 554(7692): 323-327.
Zanos, P., Thompson, S. M., Duman, R. S., Zarate, C. A., Gould, T. D. Convergent mechanisms underlying rapid antidepressant action. CNS Drugs, 2018, 32(3): 197-227.
Navarria, A., Wohleb, E. S., Voleti, B., Ota, K. T., Dutheil, S., Lepack, A. E., Dwyer, J. M., Fuchikami, M., Becker, A., Drago, F. et al. Rapid antidepressant actions of scopolamine: Role of medial prefrontal cortex and M1-subtype muscarinic acetylcholine receptors. Neurobiology of Disease, 2015, 82: 254-261.
Gerhard, D. M., Wohleb, E. S., Duman, R. S. Emerging treatment mechanisms for depression: Focus on glutamate and synaptic plasticity. Drug Discovery Today, 2016, 21(3): 454-464.
Voleti, B., Navarria, A., Liu, R. J., Banasr, M., Li, N., Terwilliger, R., Sanacora, G., Eid, T., Aghajanian, G., Duman, R. S. Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. Biological Psychiatry, 2013, 74(10): 742-749.
Caruana, D. A., Warburton, E. C., Bashir, Z. I. Induction of activity-dependent LTD requires muscarinic receptor activation in medial prefrontal cortex. The Journal of Neuroscience, 2011, 31(50): 18464-18478.
Overstreet, D. H., Friedman, E., Mathé, A. A., Yadid, G. The Flinders Sensitive Line rat: A selectively bred putative animal model of depression. Neuroscience and Biobehavioral Reviews, 2005, 29(4-5): 739-759.
Licheri, V., Talani, G., Gorule, A. A., Mostallino, M. C., Biggio, G., Sanna, E. Plasticity of GABAA receptors during pregnancy and postpartum period: From gene to function. Neural Plasticity, 2015, 2015: 170435.
Maguire, J., Mody, I. GABA(A)R plasticity during pregnancy: Relevance to postpartum depression. Neuron, 2008, 59(2): 207-213.
Mostallino, M. C., Sanna, E., Concas, A., Biggio, G., Follesa, P. Plasticity and function of extrasynaptic GABA(A) receptors during pregnancy and after delivery. Psychoneuroendocrinology, 2009, 34(Suppl 1): S74-S83.
Uzunova, V., Wrynn, A. S., Kinnunen, A., Ceci, M., Kohler, C., Uzunov, D. P. Chronic antidepressants reverse cerebrocortical allopregnanolone decline in the olfactory-bulbectomized rat. European Journal of Pharmacology, 2004, 486(1): 31-34.
Shirayama, Y., Muneoka, K., Fukumoto, M., Tadokoro, S., Fukami, G., Hashimoto, K., Iyo, M. Infusions of allopregnanolone into the hippocampus and amygdala, but not into the nucleus accumbens and medial prefrontal cortex, produce antidepressant effects on the learned helplessness rats. Hippocampus, 2011, 21(10): 1105-1113.
Nin, M. S., Ferri, M. K., Couto-Pereira, N. S., Souza, M. F., Azeredo, L. A., Agnes, G., Gomez, R., Barros, H. M. The effect of intra-nucleus accumbens administration of allopregnanolone on δ and γ2 GABA(A) receptor subunit mRNA expression in the hippocampus and on depressive-like and grooming behaviors in rats. Pharmacology, Biochemistry, and Behavior, 2012, 103(2): 359-366.
Schüle, C., Romeo, E., Uzunov, D. P., Eser, D., Di Michele, F., Baghai, T. C., Pasini, A., Schwarz, M., Kempter, H., Pupprecht, R. Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3α-hydroxysteroid dehydrogenase activity. Molelucar Psychiatry, 2006, 11(3): 261-272.
Melón, L., Hammond, R., Lewis, M., Maguire, J. A novel, synthetic, neuroactive steroid is effective at decreasing depression-like behaviors and improving maternal care in preclinical models of postpartum depression. Frontiers in Endocrinology, 2018, 9: 703.
Khisti, R. T., Chopde, C. T., Jain, S. P. Antidepressant-like effect of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one in mice forced swim test. Pharmacology, Biochemistry, and Behavior, 2000, 67(1): 137-143.
Almeida, F. B., Fonseca, A. R., Heidrich, N., Nin, M. S., Barros, H. M. T. The effect of intracerebroventricular allopregnanolone on depressive-like behaviors of rats selectively bred for high and low immobility in the forced swim test. Physiology & Behavior, 2018, 194: 246-251.
Tornese, P., Sala, N., Bonini, D., Bonifacino, T., La Via, L., Milanese, M., Treccani, G., Seguini, M., Ieraci, A., Mingardi, J. et al. Chronic mild stress induces anhedonic behavior and changes in glutamate release, BDNF trafficking and dendrite morphology only in stress vulnerable rats. The rapid restorative action of ketamine. Neurobiology of Stress, 2019, 10: 100160.
Shirayama, Y., Fujita, Y., Oda, Y., Iwata, M., Muneoka, K., Hashimoto, K. Allopregnanolone induces antidepressant-like effects through BDNF-TrkB signaling independent from AMPA receptor activation in a rat learned helplessness model of depression. Behavioural Brain Research, 2020, 390: 112670.
Bjorkholm, C., Monteggia, L. M. BDNF—a key transducer of antidepressant effects. Neuropharmacology, 2016, 102: 72-79.
Zeidan, M. P., Zomkowski, A. D., Rosa, A. O., Rodrigues, A. L., Gabilan, N. H. Evidence for imidazoline receptors involvement in the agmatine antidepressant-like effect in the forced swimming test. European Journal of Pharmacology, 2007, 565(1-3): 125-131.
Neis, V. B., Manosso, L. M., Moretti, M., Freitas, A. E., Daufenbach, J., Rodrigues, A. L. Depressive-like behavior induced by tumor necrosis factor-α is abolished by agmatine administration. Behavioural Brain Research, 2014, 261: 336-344.
Freitas, A. E., Egea, J., Buendia, I., Gómez-Rangel, V., Parada, E., Navarro, E., Casas, A. I., Wojnicz, A., Ortiz, J. A., Cuadrado, A. et al. Agmatine, by improving neuroplasticity markers and inducing Nrf2, prevents corticosterone-induced depressive-like behavior in mice. Molecular Neurobiology, 2016, 53(5): 3030-3045.
Freitas, A. E., Egea, J., Buendía, I., Navarro, E., Rada, P., Cuadrado, A., Rodrigues, A. L. S., López, M. G. Agmatine induces Nrf2 and protects against corticosterone effects in hippocampal neuronal cell line. Molecular Neurobiology, 2015, 51(3): 1504-1519.
Liu, R. J., Duman, C., Kato, T., Hare, B., Lopresto, D., Bang, E., Burgdorf, J., Moskal, J., Taylor, J., Aghajanian, G. et al. GLYX-13 produces rapid antidepressant responses with key synaptic and behavioral effects distinct from ketamine. Neuropsy-chopharmacology, 2017, 42(6): 1231-1242.
Kato, T., Fogaça, M. V., Deyama, S., Li, X. Y., Fukumoto, K., Duman, R. S. BDNF release and signaling are required for the antidepressant actions of GLYX-13. Molecular Psychiatry, 2018, 23(10): 2007-2017.
Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., Krystal, J. H. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry, 2000, 47(4): 351-354.
Fedgchin, M., Trivedi, M., Daly, E. J., Melkote, R., Lane, R., Lim, P., Vitagliano, D., Blier, P., Fava, M., Liebowitz, M. 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). The International Journal of Neuropsychopharmacology, 2019, 22(10): 616-630.
Popova, V., Daly, E. J., Trivedi, M., Cooper, K., Lane, R., Lim, P., Mazzucco, C., Hough, D., Thase, M. E., Shelton, R. C. 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. The American Journal of Psychiatry, 2019, 176(6): 428-438.
Drevets, W. C., Furey, M. L. Replication of scopolamine’s antidepressant efficacy in major depressive disorder: A randomized, placebo-controlled clinical trial. Biological Psychiatry, 2010, 67(5): 432-438.
Zhou, J., Wang, W., Yang, J., Zhu, X., Feng, L., Xiao, L., Wang, G. Scopolamine augmentation of a newly initiated escitalopram treatment for major depressive disorder: Study protocol for a randomized controlled trial. Trials, 2019, 20(1): 33.
Kanes, S., Colquhoun, H., Gunduz-Bruce, H., Raines, S., Arnold, R., Schacterle, A., Doherty, J., Epperson, C. N., Deligiannidis, K. M., Riesenberg, R. et al. Brexanolone (SAGE-547 injection) in post-partum depression: A randomised controlled trial. Lancet, 2017, 390(10093): 480-489.
Meltzer-Brody, S., Colquhoun, H., Riesenberg, R., Epperson, C. N., Deligiannidis, K. M., Rubinow, D. R., Li, H., Sankoh, A. J., Clemson, C., Schacterle, A. et al. Brexanolone injection in post-partum depression: Two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet, 2018, 392(10152): 1058-1070.
Bernstein, H. G., Stich, C., Jäger, K., Dobrowolny, H., Wick, M., Steiner, J., Veh, R., Bogerts, B., Laube, G. Agmatinase, an inactivator of the putative endogenous antidepressant agmatine, is strongly upregulated in hippocampal interneurons of subjects with mood disorders. Neuropharmacology, 2012, 62(1): 237-246.
Piletz, J. E., Halaris, A., Iqbal, O., Hoppensteadt, D., Fareed, J., Zhu, H., Sinacore, J., C., DeVane, L. Nitric oxide branch of arginine metabolism in depression: effect of venlafaxine. International Journal of Health Science, 2009, 11(4): 274-281.
Liu, Y., Lin, D., Wu, B., Zhou, W. Ketamine abuse potential and use disorder. Brain Research Bulletin, 2016, 126(pt 1): 68-73.
Bokor, G., Anderson, P. D. Ketamine: an update on its abuse. Journal of Pharmacy Practice, 2014, 27(6): 582-586.
Petersen, R. C. Scopolamine induced learning failures in man. Psychopharmacology, 1977, 52(3): 283-289.
Hasselmo, M. E., Wyble, B. P. Free recall and recognition in a network model of the hippocampus: Simulating effects of scopolamine on human memory function. Behavioural Brain Research, 1997, 89(1-2): 1-34.
Drevets, W. C., Bhattacharya, A., Furey, M. L. The antidepressant efficacy of the muscarinic antagonist scopolamine: Past findings and future directions. Advances in Pharmacology, 2020, 89: 357-386.
Stress and Brain
Pages 128-144
Cite this article:
Zhang H, Wang B, Cao X. Research progress of non-monoamine antidepressants. Stress and Brain, 2021, 1(2): 128-144.








Received: 14 March 2021
Revised: 05 July 2021
Accepted: 18 August 2021
Published: 26 November 2021
© The Author(s) 2021

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