{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:20:32Z","timestamp":1789132832850,"version":"build-2803163510"},"reference-count":55,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T00:00:00Z","timestamp":1639008000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T00:00:00Z","timestamp":1639008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Alkermes, Inc."}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Neuropsychopharmacol."],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    A combination of olanzapine and samidorphan (OLZ\/SAM) received US Food and Drug Administration approval in May 2021 for the treatment of adults with schizophrenia or bipolar I disorder. OLZ\/SAM provides the efficacy of olanzapine, while mitigating olanzapine-associated weight gain. This exploratory study characterized the metabolic profile of OLZ\/SAM in healthy volunteers to gain mechanistic insights. Volunteers received once-daily oral 10\u2009mg\/10\u2009mg OLZ\/SAM, 10\u2009mg olanzapine, or placebo for 21 days. Assessments included insulin sensitivity during an oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, other measures of glucose\/lipid metabolism, and adverse event (AE) monitoring. Treatment effects were estimated with analysis of covariance. In total, 60 subjects were randomized (double-blind; placebo,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200912; olanzapine,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200924; OLZ\/SAM,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200924). Olanzapine resulted in hyperinsulinemia and reduced insulin sensitivity during an OGTT at day 19, changes not observed with OLZ\/SAM or placebo. Insulin sensitivity, measured by hyperinsulinemic-euglycemic clamp, was decreased in all treatment groups relative to baseline, but this effect was greatest with olanzapine and OLZ\/SAM. Although postprandial (OGTT) glucose and fasting cholesterol concentrations were similarly increased with olanzapine or OLZ\/SAM, other early metabolic effects were distinct, including post-OGTT C-peptide concentrations and aspects of energy metabolism. Forty-nine subjects (81.7%) experienced at least 1 AE, most mild or moderate in severity. OLZ\/SAM appeared to mitigate some of olanzapine\u2019s unfavorable postprandial metabolic effects (e.g., hyperinsulinemia, elevated C-peptide) in this exploratory study. These findings supplement the body of evidence from completed or ongoing OLZ\/SAM clinical trials supporting its role in the treatment of schizophrenia and bipolar I disorder.\n                  <\/jats:p>","DOI":"10.1038\/s41386-021-01244-7","type":"journal-article","created":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T14:02:48Z","timestamp":1639058568000},"page":"696-703","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Insulin and glucose metabolism with olanzapine and a combination of olanzapine and samidorphan: exploratory phase 1 results in healthy volunteers"],"prefix":"10.1038","volume":"47","author":[{"given":"Frederico G. S.","family":"Toledo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8740-9014","authenticated-orcid":false,"given":"William F.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Morrow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carine","family":"Beysen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiva","family":"Bajorunas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard L.","family":"Silverman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"McDonnell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5220-2275","authenticated-orcid":false,"given":"Mark N.","family":"Namchuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2153-9382","authenticated-orcid":false,"given":"John W.","family":"Newcomer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Graham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,12,9]]},"reference":[{"key":"1244_CR1","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1056\/NEJMoa051688","volume":"353","author":"JA Lieberman","year":"2005","unstructured":"Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209\u201323.","journal-title":"N Engl J Med"},{"key":"1244_CR2","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1038\/nrendo.2011.156","volume":"8","author":"M De Hert","year":"2012","unstructured":"De Hert M, Detraux J, van Winkel R, Yu W, Correll CU. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2012;8:114\u201326.","journal-title":"Nat Rev Endocrinol"},{"key":"1244_CR3","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1176\/appi.ajp.2016.16040442","volume":"174","author":"AP Rajkumar","year":"2017","unstructured":"Rajkumar AP, Horsdal HT, Wimberley T, Cohen D, Mors O, B\u00f8rglum AD, et al. Endogenous and antipsychotic-related risks for diabetes mellitus in young people with schizophrenia: a Danish population-based cohort study. Am J Psychiatry. 2017;174:686\u201394.","journal-title":"Am J Psychiatry"},{"key":"1244_CR4","first-page":"11","volume":"42","author":"RA Baker","year":"2009","unstructured":"Baker RA, Pikalov A, Tran QV, Kremenets T, Arani RB, Doraiswamy PM. Atypical antipsychotic drugs and diabetes mellitus in the US Food and Drug Administration Adverse Event database: a systematic Bayesian signal detection analysis. Psychopharmacol Bull. 2009;42:11\u201331.","journal-title":"Psychopharmacol Bull"},{"key":"1244_CR5","doi-asserted-by":"publisher","first-page":"920","DOI":"10.4088\/JCP.v63n1010","volume":"63","author":"FD Gianfrancesco","year":"2002","unstructured":"Gianfrancesco FD, Grogg AL, Mahmoud RA, Wang RH, Nasrallah HA. Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database. J Clin Psychiatry. 2002;63:920\u201330.","journal-title":"J Clin Psychiatry"},{"key":"1244_CR6","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1001\/archpsyc.59.11.1021","volume":"59","author":"CE Koro","year":"2002","unstructured":"Koro CE, Fedder DO, L\u2019Italien GJ, Weiss S, Magder LS, Kreyenbuhl J, et al. An assessment of the independent effects of olanzapine and risperidone exposure on the risk of hyperlipidemia in schizophrenic patients. Arch Gen Psychiatry. 2002;59:1021\u20136.","journal-title":"Arch Gen Psychiatry"},{"key":"1244_CR7","doi-asserted-by":"publisher","first-page":"1686","DOI":"10.1176\/ajp.156.11.1686","volume":"156","author":"DB Allison","year":"1999","unstructured":"Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156:1686\u201396.","journal-title":"Am J Psychiatry"},{"key":"1244_CR8","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1016\/S0140-6736(13)60733-3","volume":"382","author":"S Leucht","year":"2013","unstructured":"Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013;382:951\u201362.","journal-title":"Lancet"},{"key":"1244_CR9","doi-asserted-by":"publisher","first-page":"498","DOI":"10.4088\/JCP.10m06497","volume":"73","author":"RL Berkowitz","year":"2012","unstructured":"Berkowitz RL, Patel U, Ni Q, Parks JJ, Docherty JP. The impact of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) on prescribing practices: an analysis of data from a large midwestern state. J Clin Psychiatry. 2012;73:498\u2013503.","journal-title":"J Clin Psychiatry"},{"key":"1244_CR10","doi-asserted-by":"publisher","first-page":"2345","DOI":"10.1185\/030079906X148616","volume":"22","author":"TA Ketter","year":"2006","unstructured":"Ketter TA, Haupt DW. Perceptions of weight gain and bipolar pharmacotherapy: results of a 2005 survey of physicians in clinical practice. Curr Med Res Opin. 2006;22:2345\u201353.","journal-title":"Curr Med Res Opin"},{"key":"1244_CR11","doi-asserted-by":"publisher","first-page":"e22662","DOI":"10.1371\/journal.pone.0022662","volume":"6","author":"VL Albaugh","year":"2011","unstructured":"Albaugh VL, Singareddy R, Mauger D, Lynch CJ. A double blind, placebo-controlled, randomized crossover study of the acute metabolic effects of olanzapine in healthy volunteers. PLoS ONE. 2011;6:e22662.","journal-title":"PLoS ONE"},{"key":"1244_CR12","doi-asserted-by":"publisher","first-page":"1837","DOI":"10.1176\/ajp.161.10.1837","volume":"161","author":"GM Simpson","year":"2004","unstructured":"Simpson GM, Glick ID, Weiden PJ, Romano SJ, Siu CO. Randomized, controlled, double-blind multicenter comparison of the efficacy and tolerability of ziprasidone and olanzapine in acutely ill inpatients with schizophrenia or schizoaffective disorder. Am J Psychiatry. 2004;161:1837\u201347.","journal-title":"Am J Psychiatry"},{"key":"1244_CR13","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1093\/schbul\/sbp037","volume":"37","author":"KP Grootens","year":"2011","unstructured":"Grootens KP, van Veelen NM, Peuskens J, Sabbe BG, Thys E, Buitelaar JK, et al. Ziprasidone vs olanzapine in recent-onset schizophrenia and schizoaffective disorder: results of an 8-week double-blind randomized controlled trial. Schizophr Bull. 2011;37:352\u201361.","journal-title":"Schizophr Bull"},{"key":"1244_CR14","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1097\/YIC.0000000000000052","volume":"30","author":"E Daurignac","year":"2015","unstructured":"Daurignac E, Leonard KE, Dubovsky SL. Increased lean body mass as an early indicator of olanzapine-induced weight gain in healthy men. Int Clin Psychopharmacol. 2015;30:23\u20138.","journal-title":"Int Clin Psychopharmacol"},{"key":"1244_CR15","unstructured":"Alkermes, Inc. Lybalvi [package insert]. Waltham, MA: Alkermes, Inc.; 2021."},{"key":"1244_CR16","doi-asserted-by":"publisher","first-page":"2289","DOI":"10.1016\/j.bmcl.2009.02.078","volume":"19","author":"MP Wentland","year":"2009","unstructured":"Wentland MP, Lou R, Lu Q, Bu Y, Denhardt C, Jin J, et al. Syntheses of novel high affinity ligands for opioid receptors. Bioorg Med Chem Lett. 2009;19:2289\u201394.","journal-title":"Bioorg Med Chem Lett"},{"key":"1244_CR17","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1124\/jpet.118.249839","volume":"367","author":"JM Bidlack","year":"2018","unstructured":"Bidlack JM, Knapp BI, Deaver DR, Plotnikava M, Arnelle D, Wonsey AM, et al. In vitro pharmacological characterization of buprenorphine, samidorphan, and combinations being developed as an adjunctive treatment of major depressive disorder. J Pharm Exp Ther. 2018;367:267\u201381.","journal-title":"J Pharm Exp Ther"},{"key":"1244_CR18","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1097\/JCP.0000000000000320","volume":"35","author":"MJ Shram","year":"2015","unstructured":"Shram MJ, Silverman B, Ehrich E, Sellers EM, Turncliff R. Use of remifentanil in a novel clinical paradigm to characterize onset and duration of opioid blockade by samidorphan, a potent mu-receptor antagonist. J Clin Psychopharmacol. 2015;35:242\u20139.","journal-title":"J Clin Psychopharmacol"},{"key":"1244_CR19","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1176\/appi.ajp.2018.18030280","volume":"176","author":"WF Martin","year":"2019","unstructured":"Martin WF, Correll CU, Weiden PJ, Jiang Y, Pathak S, DiPetrillo L, et al. Mitigation of olanzapine-induced weight gain with samidorphan, an opioid antagonist: a randomized double-blind phase 2 study in patients with schizophrenia. Am J Psychiatry. 2019;176:457\u201367.","journal-title":"Am J Psychiatry"},{"key":"1244_CR20","unstructured":"Potkin SG, Silverman BL, Simmons A, Jiang Y, DiPetrillo L, McDonnell D. A phase 3 study to determine the antipsychotic efficacy and safety of ALKS 3831 in adult patients with acute exacerbation of schizophrenia [poster T214]. Presented at: Annual Congress of the American College of Neuropsychopharmacology, Palm Springs, CA, 3\u20137 December, 2017."},{"key":"1244_CR21","unstructured":"Correll CU, Kahn R, Silverman B, DiPetrillo L, Graham C, Jiang Y, et al. A combination of olanzapine and samidorphan mitigates the weight gain observed with olanzapine alone: results from the phase 3 ENLIGHTEN-2 schizophrenia study [poster]. Presented at: Annual Congress of the Schizophrenia International Research Society, Orlando, FL, 10\u201314 April 2019."},{"key":"1244_CR22","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1177\/0269881119856850","volume":"33","author":"JI Cunningham","year":"2019","unstructured":"Cunningham JI, Eyerman DJ, Todtenkopf MS, Dean RL, Deaver DR, Sanchez C, et al. Samidorphan mitigates olanzapine-induced weight gain and metabolic dysfunction in rats and nonhuman primates. J Psychopharmacol. 2019;33:1303\u201316.","journal-title":"J Psychopharmacol"},{"key":"1244_CR23","doi-asserted-by":"publisher","first-page":"1168","DOI":"10.1176\/appi.ajp.2020.19121279","volume":"177","author":"CU Correll","year":"2020","unstructured":"Correll CU, Newcomer JW, Silverman B, DiPetrillo L, Graham C, Jiang Y, et al. Effects of olanzapine combined with samidorphan on weight gain in schizophrenia: a 24-week phase 3 study. Am J Psychiatry. 2020;177:1168\u201378.","journal-title":"Am J Psychiatry"},{"key":"1244_CR24","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1093\/schbul\/sbr148","volume":"39","author":"AJ Mitchell","year":"2013","unstructured":"Mitchell AJ, Vancampfort D, Sweers K, van Winkel R, Yu W, De, et al. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders-a systematic review and meta-analysis. Schizophr Bull. 2013;39:306\u201318.","journal-title":"Schizophr Bull"},{"key":"1244_CR25","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1177\/2045125312464385","volume":"3","author":"E Papanastasiou","year":"2013","unstructured":"Papanastasiou E. The prevalence and mechanisms of metabolic syndrome in schizophrenia: a review. Ther Adv Psychopharmacol. 2013;3:33\u201351.","journal-title":"Ther Adv Psychopharmacol"},{"key":"1244_CR26","unstructured":"Posner K, Brent D, Lucas C, Gould M, Stanley B, Brown G, et al. Columbia-suicide severity rating scale (C-SSRS) since last visit. Columbia University Medical Center, 2009. Available at: https:\/\/cssrs.columbia.edu\/wp-content\/uploads\/C-SSRS1-14-09-SinceLastVisit.pdf. Accessed: 31 March 2021."},{"key":"1244_CR27","doi-asserted-by":"crossref","unstructured":"American Psychiatric Publishing. Diagnostic and Statistical Manual of Mental Disorders, DSM-5. 5th edn. Washington, DC: American Psychiatric Publishing; 2013.","DOI":"10.1176\/appi.books.9780890425596"},{"key":"1244_CR28","doi-asserted-by":"publisher","first-page":"89","DOI":"10.2337\/dc06-1519","volume":"30","author":"MA Abdul-Ghani","year":"2007","unstructured":"Abdul-Ghani MA, Matsuda M, Balas B, DeFronzo RA. Muscle and liver insulin resistance indexes derived from the oral glucose tolerance test. Diabetes Care. 2007;30:89\u201394.","journal-title":"Diabetes Care"},{"key":"1244_CR29","doi-asserted-by":"publisher","first-page":"1633","DOI":"10.1038\/sj.npp.1301541","volume":"33","author":"J Sacher","year":"2008","unstructured":"Sacher J, Mossaheb N, Spindelegger C, Klein N, Geiss-Granadia T, Sauermann R, et al. Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers. Neuropsychopharmacology 2008;33:1633\u201341.","journal-title":"Neuropsychopharmacology"},{"key":"1244_CR30","doi-asserted-by":"publisher","first-page":"3232","DOI":"10.2337\/db13-0430","volume":"62","author":"KL Teff","year":"2013","unstructured":"Teff KL, Rickels MR, Grudziak J, Fuller C, Nguyen HL, Rickels K. Antipsychotic-induced insulin resistance and postprandial hormonal dysregulation independent of weight gain or psychiatric disease. Diabetes 2013;62:3232\u201340.","journal-title":"Diabetes"},{"key":"1244_CR31","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1210\/jc.2008-1815","volume":"95","author":"S Vidarsdottir","year":"2010","unstructured":"Vidarsdottir S, de Leeuw van Weenen JE, Frolich M, Roelfsema F, Romijn JA, Pijl H. Effects of olanzapine and haloperidol on the metabolic status of healthy men. J Clin Endocrinol Metab. 2010;95:118\u201325.","journal-title":"J Clin Endocrinol Metab"},{"key":"1244_CR32","first-page":"1105","volume":"31","author":"P Filakovic","year":"2007","unstructured":"Filakovic P, Koic O, Laufer D, Radanovic-Grguric L, Degmecic D, Pozgain I. Second generation antipsychotics and risk of diabetes type II-comparison between olanzapine and risperidone. Coll Antropol. 2007;31:1105\u20139.","journal-title":"Coll Antropol"},{"key":"1244_CR33","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1037\/a0020751","volume":"18","author":"Y Sato","year":"2010","unstructured":"Sato Y, Yasui-Furukori N, Furukori H, Saito M, Nakagami T, Kaneko S. A crossover study on the glucose metabolism between treatment with olanzapine and risperidone in schizophrenic patients. Exp Clin Psychopharmacol. 2010;18:445\u201350.","journal-title":"Exp Clin Psychopharmacol"},{"key":"1244_CR34","doi-asserted-by":"publisher","first-page":"E250","DOI":"10.1152\/ajpendo.00315.2017","volume":"315","author":"MR Rickels","year":"2018","unstructured":"Rickels MR, Perez EM, Peleckis AJ, Alshehabi E, Nguyen HL, Stefanovski D, et al. Contribution of parasympathetic muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia. Am J Physiol Endocrinol Metab. 2018;315:E250\u2013e7.","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"1244_CR35","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.schres.2011.06.004","volume":"131","author":"M Hahn","year":"2011","unstructured":"Hahn M, Chintoh A, Giacca A, Xu L, Lam L, Mann S, et al. Atypical antipsychotics and effects of muscarinic, serotonergic, dopaminergic and histaminergic receptor binding on insulin secretion in vivo: an animal model. Schizophr Res. 2011;131:90\u20135.","journal-title":"Schizophr Res"},{"key":"1244_CR36","doi-asserted-by":"publisher","first-page":"2070","DOI":"10.1038\/s41380-018-0344-6","volume":"25","author":"ZJ Farino","year":"2020","unstructured":"Farino ZJ, Morgenstern TJ, Maffei A, Quick M, De Solis AJ, Wiriyasermkul P, et al. New roles for dopamine D(2) and D(3) receptors in pancreatic beta cell insulin secretion. Mol Psychiatry. 2020;25:2070\u201385.","journal-title":"Mol Psychiatry"},{"key":"1244_CR37","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-020-01171-z","volume":"11","author":"D Aslanoglou","year":"2021","unstructured":"Aslanoglou D, Bertera S, S\u00e1nchez-Soto M, Benjamin Free R, Lee J, Zong W, et al. Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors. Transl Psychiatry. 2021;11:59.","journal-title":"Transl Psychiatry"},{"key":"1244_CR38","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1210\/endo-107-2-461","volume":"107","author":"E Ipp","year":"1980","unstructured":"Ipp E, Schusdziarra V, Harris V, Unger RH. Morphine-induced hyperglycemia: role of insulin and glucagon. Endocrinology 1980;107:461\u20133.","journal-title":"Endocrinology"},{"key":"1244_CR39","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1007\/BF00421864","volume":"19","author":"IC Green","year":"1980","unstructured":"Green IC, Perrin D, Pedley KC, Leslie RD, Pyke DA. Effect of enkephalins and morphine on insulin secretion from isolated rat islets. Diabetologia 1980;19:158\u201361.","journal-title":"Diabetologia"},{"key":"1244_CR40","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1055\/s-2007-1018648","volume":"15","author":"IC Green","year":"1983","unstructured":"Green IC, Ray K, Perrin D. Opioid peptide effects on insulin release and c-AMP in islets of Langerhans. Horm Metab Res. 1983;15:124\u20138.","journal-title":"Horm Metab Res"},{"key":"1244_CR41","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/0014-2999(84)90346-7","volume":"102","author":"B Ahr\u00e9n","year":"1984","unstructured":"Ahr\u00e9n B, Lundquist I. Effects of naloxone on basal and stimulated insulin secretion in the mouse. Eur J Pharm. 1984;102:135\u20139.","journal-title":"Eur J Pharm"},{"key":"1244_CR42","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1172\/JCI111560","volume":"74","author":"PM Radosevich","year":"1984","unstructured":"Radosevich PM, Williams PE, Lacy DB, McRae JR, Steiner KE, Cherrington AD, et al. Effects of morphine on glucose homeostasis in the conscious dog. J Clin Invest. 1984;74:1473\u201380.","journal-title":"J Clin Invest"},{"key":"1244_CR43","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1016\/0006-8993(81)90671-5","volume":"204","author":"GH van Loon","year":"1981","unstructured":"van Loon GH, Appel NM. beta-Endorphin-induced hyperglycemia is mediated by increased central sympathetic outflow to adrenal medulla. Brain Res. 1981;204:236\u201341.","journal-title":"Brain Res"},{"key":"1244_CR44","first-page":"191","volume":"82","author":"AM Fulghesu","year":"1993","unstructured":"Fulghesu AM, Lanzone A, Cucinelli F, Caruso A, Mancuso S. Long-term naltrexone treatment reduces the exaggerated insulin secretion in patients with polycystic ovary disease. Obstet Gynecol. 1993;82:191\u20137.","journal-title":"Obstet Gynecol"},{"key":"1244_CR45","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1016\/j.pan.2018.06.006","volume":"18","author":"A Singh","year":"2018","unstructured":"Singh A, Gibert Y, Dwyer KM. The adenosine, adrenergic and opioid pathways in the regulation of insulin secretion, beta cell proliferation and regeneration. Pancreatology 2018;18:615\u201323.","journal-title":"Pancreatology"},{"key":"1244_CR46","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/0167-4889(86)90024-8","volume":"888","author":"EJ Verspohl","year":"1986","unstructured":"Verspohl EJ, Berger U, Ammon HP. The significance of mu- and delta-receptors in rat pancreatic islets for the opioid-mediated insulin release. Biochim Biophys Acta. 1986;888:217\u201324.","journal-title":"Biochim Biophys Acta"},{"key":"1244_CR47","unstructured":"Muniyappa R, Madan R. Assessing insulin sensitivity and resistance in humans. In: Feingold KR, Anawalt B, Boyce A, editors. Endotext [Internet]. South Dartmouth, MA: MDText.com, Inc.; 2018."},{"key":"1244_CR48","first-page":"19","volume":"26","author":"G Wilcox","year":"2005","unstructured":"Wilcox G. Insulin and insulin resistance. Clin Biochem Rev. 2005;26:19\u201339.","journal-title":"Clin Biochem Rev"},{"key":"1244_CR49","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1097\/01.mco.0000172588.47811.63","volume":"8","author":"J Tonelli","year":"2005","unstructured":"Tonelli J, Kishore P, Lee DE, Hawkins M. The regulation of glucose effectiveness: how glucose modulates its own production. Curr Opin Clin Nutr Metab Care. 2005;8:450\u20136.","journal-title":"Curr Opin Clin Nutr Metab Care"},{"key":"1244_CR50","doi-asserted-by":"publisher","first-page":"1646","DOI":"10.1038\/oby.2010.6","volume":"18","author":"RJ Fountaine","year":"2010","unstructured":"Fountaine RJ, Taylor AE, Mancuso JP, Greenway FL, Byerley LO, Smith SR, et al. Increased food intake and energy expenditure following administration of olanzapine to healthy men. Obesity (Silver Spring). 2010;18:1646\u201351.","journal-title":"Obesity (Silver Spring)"},{"key":"1244_CR51","unstructured":"Cutler NR. Pharmacokinetic studies of antipsychotics in healthy volunteers versus patients. J Clin Psychiatry. 2001; 62 Suppl 5: 10\u20133; discussion 23\u20134."},{"key":"1244_CR52","unstructured":"Eli Lilly and Company. Zyprexa [package insert]. Indianapolis, IN: Eli Lilly and Company; 2018."},{"key":"1244_CR53","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1001\/jamapsychiatry.2017.1322","volume":"74","author":"J Tiihonen","year":"2017","unstructured":"Tiihonen J, Mittendorfer-Rutz E, Majak M, Mehtala J, Hoti F, Jedenius E, et al. Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29823 patients with schizophrenia. JAMA Psychiatry. 2017;74:686\u201393.","journal-title":"JAMA Psychiatry"},{"key":"1244_CR54","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1093\/ijnp\/pyz037","volume":"22","author":"S Toto","year":"2019","unstructured":"Toto S, Grohmann R, Bleich S, Frieling H, Maier HB, Greil W, et al. Psychopharmacological treatment of schizophrenia over time in 30 908 inpatients: data from the AMSP study. Int J Neuropsychopharmacol. 2019;22:560\u201373.","journal-title":"Int J Neuropsychopharmacol"},{"key":"1244_CR55","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.schres.2017.10.014","volume":"195","author":"BL Silverman","year":"2018","unstructured":"Silverman BL, Martin W, Memisoglu A, DiPetrillo L, Correll CU, Kane JM. A randomized, double-blind, placebo-controlled proof of concept study to evaluate samidorphan in the prevention of olanzapine-induced weight gain in healthy volunteers. Schizophr Res. 2018;195:245\u201351.","journal-title":"Schizophr Res"}],"container-title":["Neuropsychopharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41386-021-01244-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41386-021-01244-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41386-021-01244-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,10]],"date-time":"2023-02-10T13:14:03Z","timestamp":1676034843000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41386-021-01244-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,9]]},"references-count":55,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2022,2]]}},"alternative-id":["1244"],"URL":"https:\/\/doi.org\/10.1038\/s41386-021-01244-7","relation":{},"ISSN":["0893-133X","1740-634X"],"issn-type":[{"value":"0893-133X","type":"print"},{"value":"1740-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,9]]},"assertion":[{"value":"4 June 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 October 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 November 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 December 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"FGST has received consulting honoraria from Alkermes, Inc. BLS, WFM, YJ, and MNN were employees of Alkermes, Inc., at the time of this study. CG is an employee of Alkermes, Inc. LM and CB are employees and shareholders in ProSciento, Inc. DB was an employee of Vault Bioventures\u00a0at the time of this study and has served as a consultant for Alkermes, Inc. DM is an employee of Alkermes Pharma Ireland Ltd. JWN has received grant support from the National Institutes of Health and the Substance Abuse and Mental Health Services Administration, has served as a consultant for Alkermes, Inc., Intra-cellular Therapies, Inc., and Sunovion, and served on a Data Safety Monitoring Board for Amgen.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}