{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T19:41:18Z","timestamp":1785354078335,"version":"3.55.0"},"reference-count":86,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T00:00:00Z","timestamp":1627603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["I01BX002908"],"award-info":[{"award-number":["I01BX002908"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007201","name":"Utah Science Technology and Research","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100007201","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016284","name":"VISN 4 Mental Illness Research, Education, and Clinical Center","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100016284","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Background: Rates of major depressive disorder (MDD) increase with living at altitude. In our model, rats housed at moderate altitude (in hypobaric hypoxia) exhibit increased depression-like behavior, altered brain serotonin and a lack of antidepressant response to most selective serotonin reuptake inhibitors (SSRIs). A forebrain deficit in the bioenergetic marker creatine is noted in people living at altitude or with MDD. Methods: Rats housed at 4500 ft were given dietary creatine monohydrate (CRMH, 4% w\/w, 5 weeks) vs. un-supplemented diet, and impact on depression-like behavior, brain bioenergetics, serotonin and SSRI efficacy assessed. Results: CRMH significantly improved brain creatine in a sex-based manner. At altitude, CRMH increased serotonin levels in the female prefrontal cortex and striatum but reduced male striatal and hippocampal serotonin. Dietary CRMH was antidepressant in the forced swim test and anti-anhedonic in the sucrose preference test in only females at altitude, with motor behavior unchanged. CRMH improved fluoxetine efficacy (20 mg\/kg) in only males at altitude: CRMH + SSRI significantly improved male striatal creatine and serotonin vs. CRMH alone. Conclusions: Dietary CRMH exhibits sex-based efficacy in resolving altitude-related deficits in brain biomarkers, depression-like behavior and SSRI efficacy, and may be effective clinically for SSRI-resistant depression at altitude. This is the first study to link CRMH treatment to improving brain serotonin.<\/jats:p>","DOI":"10.3390\/ijms22158195","type":"journal-article","created":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T12:59:24Z","timestamp":1627649964000},"page":"8195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Sex-Based Impact of Creatine Supplementation on Depressive Symptoms, Brain Serotonin and SSRI Efficacy in an Animal Model of Treatment-Resistant Depression"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7228-6840","authenticated-orcid":false,"given":"Shami","family":"Kanekar","sequence":"first","affiliation":[{"name":"Diagnostic Neuroimaging, Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA"},{"name":"VISN19 MIRECC, 500 Foothill Drive, Salt Lake City, UT 84148, USA"},{"name":"Veterans Affairs Salt Lake City Health Care System, 500 Foothill Drive, Salt Lake City, UT 84148, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Ettaro","sequence":"additional","affiliation":[{"name":"Diagnostic Neuroimaging, Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Diagnostic Neuroimaging, Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik J.","family":"Ombach","sequence":"additional","affiliation":[{"name":"Diagnostic Neuroimaging, Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jadeda","family":"Brown","sequence":"additional","affiliation":[{"name":"Diagnostic Neuroimaging, Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8882-9224","authenticated-orcid":false,"given":"Cayla","family":"Lynch","sequence":"additional","affiliation":[{"name":"Diagnostic Neuroimaging, Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandni S.","family":"Sheth","sequence":"additional","affiliation":[{"name":"Diagnostic Neuroimaging, Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perry F.","family":"Renshaw","sequence":"additional","affiliation":[{"name":"Diagnostic Neuroimaging, Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA"},{"name":"VISN19 MIRECC, 500 Foothill Drive, Salt Lake City, UT 84148, USA"},{"name":"Veterans Affairs Salt Lake City Health Care System, 500 Foothill Drive, Salt Lake City, UT 84148, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1176\/appi.ps.201300059","article-title":"A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996\u20132013","volume":"65","author":"Mrazek","year":"2014","journal-title":"Psychiatr. 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