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To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. Twenty patients suffering a major depressive episode were randomized to pretreatment with oral rapamycin (6\u2009mg) or placebo 2\u2009h prior to the intravenous administration of ketamine 0.5\u2009mg\/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery\u2013\u00c5sberg Depression Rating Scale (MADRS). Rapamycin pretreatment did not alter the antidepressant effects of ketamine at the 24-h timepoint. Over the subsequent 2-weeks, we found a significant treatment by time interaction (\n                    <jats:italic>F<\/jats:italic>\n                    <jats:sub>(8,245)<\/jats:sub>\n                    \u2009=\u20092.02,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.04), suggesting a prolongation of the antidepressant effects of ketamine by rapamycin. Two weeks following ketamine administration, we found higher response (41%) and remission rates (29%) following rapamycin\u2009+\u2009ketamine compared to placebo\u2009+\u2009ketamine (13%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.04, and 7%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.003, respectively). In summary, single dose rapamycin pretreatment failed to block the antidepressant effects of ketamine, but it prolonged ketamine\u2019s antidepressant effects. This observation raises questions about the role of systemic vs. local blockade of mTORC1 in the antidepressant effects of ketamine, provides preliminary evidence that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that contribute to depression relapse after ketamine administration.\n                  <\/jats:p>","DOI":"10.1038\/s41386-020-0644-9","type":"journal-article","created":{"date-parts":[[2020,2,28]],"date-time":"2020-02-28T09:02:49Z","timestamp":1582880569000},"page":"990-997","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":181,"title":["Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin"],"prefix":"10.1038","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5783-6181","authenticated-orcid":false,"given":"Chadi G.","family":"Abdallah","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynnette A.","family":"Averill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralitza","family":"Gueorguieva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selin","family":"Goktas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prerana","family":"Purohit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohini","family":"Ranganathan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Sherif","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung-Heup","family":"Ahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak Cyril","family":"D\u2019Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Formica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Southwick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8690-8439","authenticated-orcid":false,"given":"Ronald S.","family":"Duman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard","family":"Sanacora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John H.","family":"Krystal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,24]]},"reference":[{"key":"644_CR1","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1176\/appi.ajp.2013.13030392","volume":"170","author":"JW Murrough","year":"2013","unstructured":"Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, et al. 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