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The American Brain Society"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Neuropsychopharmacol."],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    NMDA receptor antagonists have a vital role in extinction, learning, and reconsolidation processes. During the reconsolidation window, memories are activated into a labile state and can be reconsolidated in an altered form. This concept might have significant clinical implications in treating PTSD. In this pilot study we tested the potential of a single infusion of ketamine, followed by brief exposure therapy, to enhance post-retrieval extinction of PTSD trauma memories. 27 individuals diagnosed with PTSD were randomly assigned to receive either ketamine (0.5\u2009mg\/kg 40\u2009min;\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u200914) or midazolam (0.045\u2009mg\/kg;\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u200913) after retrieval of the traumatic memory. 24\u2009h following infusion, participants received a four-day trauma-focused psychotherapy. Symptoms and brain activity were assessed before treatment, at the end of treatment, and at 30-day follow-up. Amygdala activation to trauma scripts (a major biomarker of fear response) served as the main study outcome. Although PTSD symptoms improved equally in both groups, post-treatment, ketamine recipients showed a lower amygdala (\u22120.33, sd\u2009=\u20090.13, 95%HDI [\u22120.56,\u22120.04]) and hippocampus (\u22120.3 (sd\u2009=\u20090.19), 95%HDI [\u22120.65, 0.04]; marginal effect) reactivation to trauma memories, compared to midazolam recipients. Post-retrieval ketamine administration was also associated with decreased connectivity between the amygdala and hippocampus (\u22120.28, sd\u2009=\u20090.11, 95%HDI [\u22120.46, \u22120.11]), with no change in amygdala-vmPFC connectivity. Moreover, reduction in fractional anisotropy in bi-lateral uncinate fasciculus was seen in the Ketamine recipients compared with the midazolam recipients (right: post-treatment: \u22120.01108, 95% HDI [\u22120.0184,\u22120.003]; follow-up: \u22120.0183, 95% HDI [\u22120.02719,\u22120.0107]; left: post-treatment: \u22120.019, 95% HDI [\u22120.028,\u22120.011]; follow-up: \u22120.017, 95% HDI [\u22120.026,\u22120.007]). Taken together it is possible that ketamine may enhance post-retrieval extinction of the original trauma memories in humans. These preliminary findings show promising direction toward the capacity to rewrite human traumatic memories and modulate the fear response for at least 30 days post-extinction. When combined with psychotherapy for PTSD, further investigation of ketamine dose, timing of administration, and frequency of administration, is warranted.\n                  <\/jats:p>","DOI":"10.1038\/s41386-023-01606-3","type":"journal-article","created":{"date-parts":[[2023,6,3]],"date-time":"2023-06-03T08:02:07Z","timestamp":1685779327000},"page":"1648-1658","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Long term structural and functional neural changes following a single infusion of Ketamine in PTSD"],"prefix":"10.1038","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5211-7946","authenticated-orcid":false,"given":"Or","family":"Duek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nachshon","family":"Korem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3141-1326","authenticated-orcid":false,"given":"Ben","family":"Kelmendi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelley","family":"Amen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Gordon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison","family":"Milne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6952-1726","authenticated-orcid":false,"given":"John H.","family":"Krystal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ifat","family":"Levy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6066-9406","authenticated-orcid":false,"given":"Ilan","family":"Harpaz-Rotem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,6,3]]},"reference":[{"key":"1606_CR1","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1038\/35021052","volume":"406","author":"K Nader","year":"2000","unstructured":"Nader K, Schafe GE, Le Doux JE. 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US Patent No. 8,778,979 B2 Patent Issue Date: July 15, 2014. US Patent Application No. 15\/695,164: Filing Date: 09\/05\/2017; Intranasal Administration of Ketamine to Treat Depression United States Patent Number: 9592207, Issue date: 3\/14\/2017. Licensed to Janssen Research & Development. Other interests J.K: Consultant (the Individual Consultant Agreements listed below are less than $5,000 per year): Aptinyx, Inc.; Atai Life Sciences; AstraZeneca Pharmaceuticals; Biogen, Idec, MA; Biomedisyn Corporation; Bionomics, Limited (Australia); Boehringer Ingelheim International; Cadent Therapeutics, Inc.; Clexio Bioscience, Ltd.; COMPASS Pathways, Limited, United Kingdom; Concert Pharmaceuticals, Inc.; Epiodyne, Inc.; EpiVario, Inc.; Greenwich Biosciences, Inc.; Heptares Therapeutics, Limited (UK); Janssen Research & Development; Jazz Pharmaceuticals, Inc.; Otsuka America Pharmaceutical, Inc.; Perception Neuroscience Holdings, Inc.; Spring Care, Inc.; Sunovion; Pharmaceuticals, Inc.; Takeda Industries; Taisho Pharmaceutical Co., Ltd. Board of Directors: Freedom Biosciences, Inc. Stock: Biohaven Pharmaceuticals; Sage Pharmaceuticals.; Spring Care, Inc. Stock Options: Biohaven Pharmaceuticals Medical Sciences; EpiVario, Inc.; RBNC Therapeutics, Inc.; Terran Biosciences, Inc.; Tempero Bio, Inc. Patents and Inventions: Seibyl JP, Krystal JH, Charney DS. Dopamine and noradrenergic reuptake inhibitors in treatment of schizophrenia. US Patent #:5,447,948.September 5, 1995; Zarate, C, Charney, DS, Manji, HK, Mathew, Sanjay J, Krystal, JH, Yale University \u201cMethods for Treating Suicidal Ideation\u201d, Patent Application No. 15\/379,013 filed on December 14, 2016 by Yale University Office of Cooperative Research; Arias A, Petrakis I, Krystal JH. \u2013 Composition and methods to treat addiction. Provisional Use Patent Application no.61\/973\/961. April 2, 2014. Filed by Yale University Office of Cooperative Research; Chekroud, A., Gueorguieva, R., & Krystal, JH. \u201cTreatment Selection for Major Depressive Disorder\u201d [filing date 3<sup>rd<\/sup> June 2016, USPTO docket number Y0087.70116US00]. Provisional patent submission by Yale University; Gihyun, Yoon, Petrakis I, Krystal JH \u2013 Compounds, Compositions and Methods for Treating or Preventing Depression and Other Diseases. U. S. Provisional Patent Application No. 62\/444,552, filed on January 10, 2017 by Yale University Office of Cooperative Research OCR 7088 US01; Abdallah, C, Krystal, JH, Duman, R, Sanacora, G. Combination Therapy for Treating or Preventing Depression or Other Mood Diseases. U.S. Provisional Patent Application No. 62\/719,935 filed on August 20, 2018 by Yale University Office of Cooperative Research OCR 7451 US01; John Krystal, Godfrey Pearlson, Stephanie O\u2019Malley, Marc Potenza, Fabrizio Gasparini, Baltazar Gomez-Mancilla, Vincent Malaterre. Mavoglurant in treating gambling and gaming disorders. U.S. Provisional Patent Application No. 63\/125,181filed on December 14, 2020 by Yale University Office of Cooperative Research OCR 8065 US00 NON Federal Research Support: AstraZeneca Pharmaceuticals provides the drug, Saracatinib, for research related to NIAAA grant \u201cCenter for Translational Neuroscience of Alcoholism [CTNA-4]; Novartis provides the drug, Mavoglurant, for research related to NIAAA grant \u201cCenter for Translational Neuroscience of Alcoholism [CTNA-4]; Cerevel provides the drug PF-06412562 for A Translational and Neurocomputational Evaluation of a D1R Partial Agonist for Schizophrenia (1 U01 MH121766-01). Scientific Advisory Board: Biohaven Pharmaceuticals; BioXcel Therapeutics, Inc. (Clinical Advisory Board); Cadent Therapeutics, Inc. (Clinical Advisory Board); Cerevel Therapeutics, LLC; EpiVario, Inc.; Eisai, Inc.; Jazz Pharmaceuticals, Inc.; Lohocla Research Corporation; Novartis Pharmaceuticals Corporation; PsychoGenics, Inc.; RBNC Therapeutics, Inc.; Tempero Bio, Inc.; Terran Biosciences, Inc.; Income Greater than $10,000: Editor - Biological Psychiatry. OD is consultant for Madrigal Mental Care. All remaining authors have nothing to disclose. I.H.R receives funding from <i>Boehringer Ingelheim Pharma GmbH & Co. KG<\/i> through Investigator-Initiated Research into \u201cSubtyping PTSD - Precision Psychiatry\u201d.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}