{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T04:15:53Z","timestamp":1787890553017,"version":"build-2784847793"},"reference-count":31,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T00:00:00Z","timestamp":1669593600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["CIHR # PJT-153262"],"award-info":[{"award-number":["CIHR # PJT-153262"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000241","name":"Physicians\u2019 Services Incorporated Foundation","doi-asserted-by":"publisher","award":["PSI Grant #18-33"],"award-info":[{"award-number":["PSI Grant #18-33"]}],"id":[{"id":"10.13039\/501100000241","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ontario Graduate Scholarship"},{"name":"Banting and Best Diabetes Centre Novo Nordisk Graduate Studentship"},{"name":"Ontario Graduate Scholarship"},{"name":"Cleghorn Fellowship in Schizophrenia Research"},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100014405","name":"CAMH Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100014405","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003579","name":"University of Toronto","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003579","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100018679","name":"HLS Therapeutics","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100018679","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015070","name":"Department of Psychiatry, University of Toronto","doi-asserted-by":"crossref","award":["Academic Scholars Award"],"award-info":[{"award-number":["Academic Scholars Award"]}],"id":[{"id":"10.13039\/100015070","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Banting and BestDiabetes Centre"},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"name":"PSIFoundation, Ontario"},{"DOI":"10.13039\/100015223","name":"the Danish Diabetes Academy","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100015223","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Antipsychotics (APs) are the cornerstone of treatment for schizophrenia (SCZ) but are unfortunately associated with serious metabolic adverse effects including weight gain and type 2 diabetes. The pathophysiology of AP-induced metabolic dysfunction is largely undetermined. Brain insulin resistance has been posited to be at the cross-roads of many cognitive and metabolic disorders, and disruption of central insulin action has emerged as a possible explanatory mechanism underlying AP induced metabolic dysfunction. Previous studies suggest that change in neuroimaging-based parameters with intranasal insulin administration can be leveraged to investigate brain insulin resistance. In this proof-of-concept study, we will utilize neural signatures of insulin action in the brain to examine if APs disrupt brain insulin signaling. It is hypothesized that: 1) intranasal insulin (INI), but not intranasal placebo (INP), will change cerebral blood flow and resting state connectivity, as well as increase glutamate levels in the striatum and dorsolateral prefrontal cortex; 2) oral olanzapine (OLA), but not oral placebo (PL), will inhibit the effect of INI on these parameters. Thirty-two healthy volunteers will undergo a single blind, cross-over design, wherein all participants receive the following four treatment combinations, 2\u20136 weeks apart, in a random sequence: INP + PL, INP + OLA, INI + PL, and INI + OLA. Participants will undergo an MRI-based assay of brain insulin resistance 15 minutes after administering 160 IU INI or INP. The scanning protocol includes resting and task-based functional MRI, arterial spin labelling, and proton magnetic resonance spectroscopy. Demonstrating that OLA can acutely induce brain insulin resistance is clinically relevant to metabolic health in SCZ. Evidence of brain insulin resistance induced by acute AP dosing can inform the early use of adjunctive insulin sensitizers for the treatment of metabolic comorbidities associated with AP treatment in severe mental illness.<\/jats:p>\n<jats:p>Trial registration<\/jats:p>\n<jats:p><jats:bold>ClinicalTrials.gov Registration<\/jats:bold>: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03741478\" xlink:type=\"simple\">NCT03741478<\/jats:ext-link>.<\/jats:p>","DOI":"10.1371\/journal.pone.0277211","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T18:43:54Z","timestamp":1669661034000},"page":"e0277211","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Investigating the effects of antipsychotics on brain insulin action: Study protocol for a multi-modality magnetic resonance imaging (MRI) study in healthy controls"],"prefix":"10.1371","volume":"17","author":[{"given":"Nicolette","family":"Stogios","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie","family":"Hamel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9075-1761","authenticated-orcid":true,"given":"Marcos","family":"Sanches","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Remington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aristotle","family":"Voineskos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satya","family":"Dash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel","family":"Graff-Guerrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Hahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2705-5146","authenticated-orcid":true,"given":"Sri Mahavir","family":"Agarwal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,11,28]]},"reference":[{"issue":"suppl 1","key":"pone.0277211.ref001","doi-asserted-by":"crossref","DOI":"10.4088\/JCP.10075su1.01","article-title":"Antipsychotics in the Treatment of Schizophrenia","volume":"72","author":"R. Tandon","year":"2011","journal-title":"The Journal of Clinical Psychiatry"},{"key":"pone.0277211.ref002","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2014\/656370","article-title":"Second-Generation Antipsychotics and Extrapyramidal Adverse Effects","volume":"2014","author":"N. Divac","year":"2014","journal-title":"BioMed Research International"},{"issue":"4","key":"pone.0277211.ref003","doi-asserted-by":"crossref","first-page":"E225","DOI":"10.9778\/cmajo.20140009","article-title":"Dispensed prescriptions for quetiapine and other second-generation antipsychotics in Canada from 2005 to 2012: a descriptive study","volume":"2","author":"T. Pringsheim","year":"2014","journal-title":"CMAJ Open"},{"issue":"1","key":"pone.0277211.ref004","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1093\/bmb\/ldv017","article-title":"Antipsychotic medication in schizophrenia: a review","volume":"114","author":"J. Lally","year":"2015","journal-title":"British Medical Bulletin"},{"issue":"11","key":"pone.0277211.ref005","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1176\/ajp.156.11.1686","article-title":"Antipsychotic-induced weight gain: a comprehensive research synthesis","volume":"156","author":"D.B. Allison","year":"1999","journal-title":"Am J Psychiatry"},{"issue":"8","key":"pone.0277211.ref006","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1177\/070674370605100803","article-title":"The metabolic effects of antipsychotic medications","volume":"51","author":"J.W. Newcomer","year":"2006","journal-title":"Can J Psychiatry"},{"key":"pone.0277211.ref007","article-title":"Metabolic adverse effects of off-label use of second-generation antipsychotics in the adult population: a systematic review and meta-analysis","author":"N. Stogios","year":"2021","journal-title":"Neuropsychopharmacology"},{"issue":"6","key":"pone.0277211.ref008","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1097\/JCP.0b013e31829e8333","article-title":"Acute effects of single-dose olanzapine on metabolic, endocrine, and inflammatory markers in healthy controls","volume":"33","author":"M.K. Hahn","year":"2013","journal-title":"J Clin Psychopharmacol"},{"issue":"1","key":"pone.0277211.ref009","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1152\/ajpendo.00164.2018","article-title":"Antipsychotics and glucose metabolism: how brain and body collide","volume":"316","author":"C. Kowalchuk","year":"2019","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"4","key":"pone.0277211.ref010","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1152\/physrev.00032.2015","article-title":"Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans","volume":"96","author":"S. Kullmann","year":"2016","journal-title":"Physiol Rev"},{"issue":"12","key":"pone.0277211.ref011","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1038\/nm1202-798","article-title":"Hypothalamic insulin signaling is required for inhibition of glucose production","volume":"8","author":"S. Obici","year":"2002","journal-title":"Nat Med"},{"issue":"4","key":"pone.0277211.ref012","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.cmet.2012.09.005","article-title":"Insulin activates Erk1\/2 signaling in the dorsal vagal complex to inhibit glucose production","volume":"16","author":"B.M. Filippi","year":"2012","journal-title":"Cell Metab"},{"issue":"3","key":"pone.0277211.ref013","doi-asserted-by":"crossref","first-page":"766","DOI":"10.2337\/db14-0685","article-title":"Intranasal insulin suppresses endogenous glucose production in humans compared with placebo in the presence of similar venous insulin concentrations","volume":"64","author":"S. Dash","year":"2015","journal-title":"Diabetes"},{"issue":"6","key":"pone.0277211.ref014","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1503\/jpn.170092","article-title":"In male rats, the ability of central insulin to suppress glucose production is impaired by olanzapine, whereas glucose uptake is left intact","volume":"42","author":"C. Kowalchuk","year":"2017","journal-title":"J Psychiatry Neurosci"},{"issue":"1","key":"pone.0277211.ref015","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1038\/s41598-017-01907-w","article-title":"Intranasal insulin enhances brain functional connectivity mediating the relationship between adiposity and subjective feeling of hunger","volume":"7","author":"S. Kullmann","year":"2017","journal-title":"Sci Rep"},{"issue":"1","key":"pone.0277211.ref016","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1210\/jc.2017-01976","article-title":"Dose-Dependent Effects of Intranasal Insulin on Resting-State Brain Activity","volume":"103","author":"S. Kullmann","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"pone.0277211.ref017","doi-asserted-by":"crossref","first-page":"751","DOI":"10.2337\/dc13-1672","article-title":"Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes","volume":"37","author":"V. Novak","year":"2014","journal-title":"Diabetes Care"},{"issue":"9","key":"pone.0277211.ref018","doi-asserted-by":"crossref","first-page":"2787","DOI":"10.2337\/dc12-1437","article-title":"The effect of insulin infusion on the metabolites in cerebral tissues assessed with proton magnetic resonance spectroscopy in young healthy subjects with high and low insulin sensitivity","volume":"36","author":"M. Karczewska-Kupczewska","year":"2013","journal-title":"Diabetes Care"},{"issue":"2","key":"pone.0277211.ref019","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.euroneuro.2017.12.002","article-title":"Reduced insulin sensitivity may be related to less striatal glutamate: An (1)H-MRS study in healthy non-obese humans","volume":"28","author":"F. Caravaggio","year":"2018","journal-title":"Eur Neuropsychopharmacol"},{"issue":"3","key":"pone.0277211.ref020","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1111\/j.1463-1326.2011.01490.x","article-title":"Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism","volume":"14","author":"V. Ott","year":"2012","journal-title":"Diabetes, Obesity and Metabolism"},{"issue":"10","key":"pone.0277211.ref021","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1001\/jamapsychiatry.2013.289","article-title":"Glutamate Levels in the Associative Striatum Before and After 4 Weeks of Antipsychotic Treatment in First-Episode Psychosis","volume":"70","author":"C. De La Fuente-Sandoval","year":"2013","journal-title":"JAMA Psychiatry"},{"issue":"9","key":"pone.0277211.ref022","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1038\/npp.2011.65","article-title":"Higher levels of glutamate in the associative-striatum of subjects with prodromal symptoms of schizophrenia and patients with first-episode psychosis","volume":"36","author":"C. De La Fuente-sandoval","year":"2011","journal-title":"Neuropsychopharmacology"},{"key":"pone.0277211.ref023","doi-asserted-by":"crossref","first-page":"107655","DOI":"10.1016\/j.neuropharm.2019.05.032","article-title":"Brain insulin action: Implications for the treatment of schizophrenia","volume":"168","author":"S.M. Agarwal","year":"2020","journal-title":"Neuropharmacology"},{"key":"pone.0277211.ref024","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.bbr.2017.09.033","article-title":"Insulin modulates hippocampally-mediated spatial working memory via glucose transporter-4","volume":"338","author":"J. Pearson-Leary","year":"2018","journal-title":"Behav Brain Res"},{"issue":"6","key":"pone.0277211.ref025","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.2337\/dc14-2319","article-title":"Selective insulin resistance in homeostatic and cognitive control brain areas in overweight and obese adults","volume":"38","author":"S. Kullmann","year":"2015","journal-title":"Diabetes Care"},{"issue":"5","key":"pone.0277211.ref026","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1080\/1357650X.2012.744414","article-title":"Revisiting Geschwind\u2019s hypothesis on brain lateralisation: a functional MRI study of digit ratio (2D:4D) and sex interaction effects on spatial working memory","volume":"18","author":"S.V. Kalmady","year":"2013","journal-title":"Laterality"},{"issue":"2","key":"pone.0277211.ref027","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1037\/1040-3590.8.2.145","article-title":"Revision of the Brief Visuospatial Memory Test: Studies of normal performance, reliability, and validity","volume":"8","author":"R.H.B Benedict","year":"1996","journal-title":"Psychological Assessment"},{"issue":"6","key":"pone.0277211.ref028","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1002\/1097-4679(198611)42:6<918::AID-JCLP2270420617>3.0.CO;2-Y","article-title":"Normative data stratified by age and sex for 12 neuropsychological tests","volume":"42","author":"Lorne T. Yeudall","year":"1986","journal-title":"Journal of Clinical Psychology"},{"issue":"5","key":"pone.0277211.ref029","doi-asserted-by":"crossref","first-page":"463","DOI":"10.3758\/BF03203313","article-title":"An automated version of the digit symbol substitution test (DSST)","volume":"14","author":"D.R. McLeod","year":"1982","journal-title":"Behavior Research Methods & Instrumentation"},{"issue":"3","key":"pone.0277211.ref030","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/BF00428325","article-title":"Impaired performance and sedation after a single dose of lorazepam","volume":"66","author":"S.E. File","year":"1979","journal-title":"Psychopharmacology (Berl)"},{"issue":"4","key":"pone.0277211.ref031","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1111\/j.1469-8986.1973.tb00801.x","article-title":"Quantification of sleepiness: a new approach","volume":"10","author":"E. Hoddes","year":"1973","journal-title":"Psychophysiology"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0277211","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T18:44:59Z","timestamp":1669661099000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0277211"}},"subtitle":[],"editor":[{"given":"Vanessa","family":"Carels","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,11,28]]},"references-count":31,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11,28]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0277211","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,28]]}}}