{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:38:35Z","timestamp":1790127515556,"version":"4.0.1"},"reference-count":63,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,11,16]],"date-time":"2017-11-16T00:00:00Z","timestamp":1510790400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,11,16]],"date-time":"2017-11-16T00:00:00Z","timestamp":1510790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Accumulating evidence suggests a key role of the gut\u2013microbiota\u2013brain axis in the antidepressant actions of certain compounds. Ketamine, an <jats:italic>N<\/jats:italic>-methyl-D-aspartate receptor (NMDAR) antagonist, showed rapid and sustained antidepressant effects in treatment-resistant depressed patients. In contrast, another NMDAR antagonist, lanicemine, did not exhibit antidepressant effects in such patients. (<jats:italic>R<\/jats:italic>)-ketamine, the (<jats:italic>R<\/jats:italic>)-enantiomer of ketamine, has rapid-acting and long-lasting antidepressant effects in rodent models of depression. Here we compared the effects of (<jats:italic>R<\/jats:italic>)-ketamine and lanicemine on depression-like phenotype and the composition of the gut microbiota in susceptible mice after chronic social defeat stress (CSDS). In behavioral tests, (<jats:italic>R<\/jats:italic>)-ketamine showed antidepressant effects in the susceptible mice, whereas lanicemine did not. The 16S ribosomal RNA gene sequencing of feces demonstrated that (<jats:italic>R<\/jats:italic>)-ketamine, but not lanicemine, significantly attenuated the altered levels of <jats:italic>Bacteroidales<\/jats:italic>, <jats:italic>Clostridiales<\/jats:italic> and <jats:italic>Ruminococcaceae<\/jats:italic> in the susceptible mice after CSDS. At the genus level, (<jats:italic>R<\/jats:italic>)-ketamine significantly attenuated the marked increase of <jats:italic>Clostridium<\/jats:italic> in the susceptible mice. In contrast, the effects of lanicemine were less potent than those of (<jats:italic>R<\/jats:italic>)-ketamine. This study suggests that the antidepressant effects of (<jats:italic>R<\/jats:italic>)-ketamine might be partly mediated by the restoration of altered compositions of the gut microbiota in a CSDS model.<\/jats:p>","DOI":"10.1038\/s41598-017-16060-7","type":"journal-article","created":{"date-parts":[[2017,11,10]],"date-time":"2017-11-10T12:57:07Z","timestamp":1510318627000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":120,"title":["Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model"],"prefix":"10.1038","volume":"7","author":[{"given":"Youge","family":"Qu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2982-8824","authenticated-orcid":false,"given":"Qian","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,11,16]]},"reference":[{"key":"16060_CR1","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/S0006-3223(99)00230-9","volume":"47","author":"RM Berman","year":"2000","unstructured":"Berman, R. M. et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry \n                           47, 351\u2013354 (2000).","journal-title":"Biol Psychiatry"},{"key":"16060_CR2","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1001\/archpsyc.63.8.856","volume":"63","author":"CA Zarate Jr","year":"2006","unstructured":"Zarate, C. A. Jr. et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry \n                           63, 856\u2013864 (2006).","journal-title":"Arch Gen Psychiatry"},{"key":"16060_CR3","doi-asserted-by":"publisher","first-page":"1134","DOI":"10.1176\/appi.ajp.2013.13030392","volume":"170","author":"JW Murrough","year":"2013","unstructured":"Murrough, J. W. et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry \n                           170, 1134\u20131142 (2013).","journal-title":"Am J Psychiatry"},{"key":"16060_CR4","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1001\/archgenpsychiatry.2010.90","volume":"67","author":"N Diazgranados","year":"2010","unstructured":"Diazgranados, N. et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry \n                           67, 793\u2013802 (2010).","journal-title":"Arch Gen Psychiatry"},{"key":"16060_CR5","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1016\/j.biopsych.2011.12.010","volume":"71","author":"CA Zarate","year":"2012","unstructured":"Zarate, C. A. et al. Replication of ketamine\u2019s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry \n                           71, 939\u2013946 (2012).","journal-title":"Biol Psychiatry"},{"key":"16060_CR6","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1176\/appi.ajp.2015.15040465","volume":"172","author":"DJ Newport","year":"2015","unstructured":"Newport, D. J. et al. APA Council of Research Task Force on Novel Biomarkers and Treatments (2015): Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry \n                           172, 950\u2013966 (2015).","journal-title":"Am J Psychiatry"},{"key":"16060_CR7","doi-asserted-by":"publisher","first-page":"1459","DOI":"10.1017\/S0033291716000064","volume":"46","author":"T Kishimoto","year":"2016","unstructured":"Kishimoto, T. et al. Single-dose infusion ketamine and non-ketamine N-methyl-D-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med \n                           46, 1459\u20131472 (2016).","journal-title":"Psychol Med"},{"key":"16060_CR8","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.4088\/JCP.09m05327blu","volume":"71","author":"N Diazgranados","year":"2010","unstructured":"Diazgranados, N. et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry \n                           71, 1605\u20131611 (2010).","journal-title":"J Clin Psychiatry"},{"key":"16060_CR9","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1002\/da.22253","volume":"31","author":"RB Price","year":"2014","unstructured":"Price, R. B. et al. Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depress Anxiety \n                           31, 335\u2013343 (2014).","journal-title":"Depress Anxiety"},{"key":"16060_CR10","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1001\/archpsyc.1994.03950030035004","volume":"51","author":"JH Krystal","year":"1994","unstructured":"Krystal, J. H. et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry \n                           51, 199\u2013241 (1994).","journal-title":"Arch Gen Psychiatry"},{"key":"16060_CR11","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1176\/appi.ajp.2016.16010037","volume":"173","author":"JB Singh","year":"2016","unstructured":"Singh, J. B. et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant repression. Am J Psychiatry \n                           173, 816\u2013826 (2016).","journal-title":"Am J Psychiatry"},{"key":"16060_CR12","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1038\/nm.4050","volume":"22","author":"RS Duman","year":"2016","unstructured":"Duman, R. S., Aghajanian, G. K., Sanacora, G. & Krystal, J. H. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med \n                           22, 238\u2013249 (2016).","journal-title":"Nat Med"},{"key":"16060_CR13","doi-asserted-by":"publisher","first-page":"2449","DOI":"10.1017\/S0033291716000969","volume":"46","author":"K Hashimoto","year":"2016","unstructured":"Hashimoto, K. R-ketamine: a rapid-onset and sustained antidepressant without risk of brain toxicity. 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Eur Arch Psychiatry Clin Neurosci \n                           267, 173\u2013176 (2017).","journal-title":"Eur Arch Psychiatry Clin Neurosci"},{"key":"16060_CR32","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.biopsych.2012.10.019","volume":"74","author":"CA Zarate Jr.","year":"2013","unstructured":"Zarate, C. A. Jr. et al. A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression. Biol Psychiatry \n                           74, 257\u2013264 (2013).","journal-title":"Biol Psychiatry"},{"key":"16060_CR33","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1038\/mp.2013.130","volume":"19","author":"G Sanacora","year":"2014","unstructured":"Sanacora, G. et al. Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects. 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Bifidobacterium in the gut microbiota confer resilience to chronic social defeat stress in mice. Sci Rep \n                           7, 45942 (2017).","journal-title":"Sci Rep"},{"key":"16060_CR43","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2017.112","volume":"7","author":"JC Zhang","year":"2017","unstructured":"Zhang, J. C. et al. Blockade of interleukin-6 receptor in the periphery promotes rapid and sustained antidepressant actions: a possible role of gut-microbiota-brain axis. Transl Psychiatry \n                           7, e1138 (2017).","journal-title":"Transl Psychiatry"},{"key":"16060_CR44","doi-asserted-by":"crossref","unstructured":"Burokas A et al. Biol Psychiatry \n                           82, 472\u2013487 (2017).","DOI":"10.1016\/j.biopsych.2016.12.031"},{"key":"16060_CR45","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.jad.2016.09.012","volume":"208","author":"D Macedo","year":"2017","unstructured":"Macedo, D. et al. 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Dr. Hashimoto has received research support from Dainippon Sumitomo, Mochida, Otsuka, and Taisho. Other authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"15725"}}