Insulin and glucose metabolism with olanzapine and a combination of olanzapine and samidorphan: exploratory phase 1 results in healthy volunteers.
Journal
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
ISSN: 1740-634X
Titre abrégé: Neuropsychopharmacology
Pays: England
ID NLM: 8904907
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
04
06
2021
accepted:
19
11
2021
revised:
15
10
2021
pubmed:
11
12
2021
medline:
3
3
2022
entrez:
10
12
2021
Statut:
ppublish
Résumé
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 mg/10 mg OLZ/SAM, 10 mg 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 = 12; olanzapine, n = 24; OLZ/SAM, n = 24). 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's 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.
Identifiants
pubmed: 34887529
doi: 10.1038/s41386-021-01244-7
pii: 10.1038/s41386-021-01244-7
pmc: PMC8782841
doi:
Substances chimiques
Antipsychotic Agents
0
Insulin
0
Narcotic Antagonists
0
Naltrexone
5S6W795CQM
3-carboxamido-4-hydroxynaltrexone
7W2581Z5L8
Glucose
IY9XDZ35W2
Olanzapine
N7U69T4SZR
Types de publication
Clinical Trial, Phase I
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
696-703Informations de copyright
© 2021. The Author(s).
Références
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;353:1209–23.
pubmed: 16172203
doi: 10.1056/NEJMoa051688
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;8:114–26.
doi: 10.1038/nrendo.2011.156
Rajkumar AP, Horsdal HT, Wimberley T, Cohen D, Mors O, Børglum 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;174:686–94.
pubmed: 28103712
doi: 10.1176/appi.ajp.2016.16040442
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;42:11–31.
pubmed: 19204649
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;63:920–30.
pubmed: 12416602
doi: 10.4088/JCP.v63n1010
Koro CE, Fedder DO, L’Italien 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;59:1021–6.
pubmed: 12418935
doi: 10.1001/archpsyc.59.11.1021
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;156:1686–96.
pubmed: 10553730
doi: 10.1176/ajp.156.11.1686
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;382:951–62.
pubmed: 23810019
doi: 10.1016/S0140-6736(13)60733-3
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;73:498–503.
pubmed: 22226332
doi: 10.4088/JCP.10m06497
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;22:2345–53.
pubmed: 17257449
doi: 10.1185/030079906X148616
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.
pubmed: 21857944
pmcid: 3153475
doi: 10.1371/journal.pone.0022662
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;161:1837–47.
pubmed: 15465981
doi: 10.1176/ajp.161.10.1837
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;37:352–61.
pubmed: 19542525
doi: 10.1093/schbul/sbp037
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;30:23–8.
pubmed: 25350366
doi: 10.1097/YIC.0000000000000052
Alkermes, Inc. Lybalvi [package insert]. Waltham, MA: Alkermes, Inc.; 2021.
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;19:2289–94.
pubmed: 19282177
pmcid: 2791460
doi: 10.1016/j.bmcl.2009.02.078
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;367:267–81.
doi: 10.1124/jpet.118.249839
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;35:242–9.
pubmed: 25928699
pmcid: 4415969
doi: 10.1097/JCP.0000000000000320
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;176:457–67.
pubmed: 30845818
doi: 10.1176/appi.ajp.2018.18030280
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, 3–7 December, 2017.
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, 10–14 April 2019.
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;33:1303–16.
pubmed: 31294646
pmcid: 6764014
doi: 10.1177/0269881119856850
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;177:1168–78.
pubmed: 32791894
doi: 10.1176/appi.ajp.2020.19121279
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;39:306–18.
pubmed: 22207632
doi: 10.1093/schbul/sbr148
Papanastasiou E. The prevalence and mechanisms of metabolic syndrome in schizophrenia: a review. Ther Adv Psychopharmacol. 2013;3:33–51.
pubmed: 23983991
pmcid: 3736963
doi: 10.1177/2045125312464385
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.
American Psychiatric Publishing. Diagnostic and Statistical Manual of Mental Disorders, DSM-5. 5th edn. Washington, DC: American Psychiatric Publishing; 2013.
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;30:89–94.
pubmed: 17192339
doi: 10.2337/dc06-1519
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;33:1633–41.
pubmed: 17712347
doi: 10.1038/sj.npp.1301541
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;62:3232–40.
pubmed: 23835329
pmcid: 3749337
doi: 10.2337/db13-0430
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;95:118–25.
pubmed: 19906788
doi: 10.1210/jc.2008-1815
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;31:1105–9.
pubmed: 18217467
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;18:445–50.
pubmed: 20939648
doi: 10.1037/a0020751
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–e7.
pubmed: 29351487
doi: 10.1152/ajpendo.00315.2017
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;131:90–5.
pubmed: 21696923
doi: 10.1016/j.schres.2011.06.004
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;25:2070–85.
pubmed: 30626912
doi: 10.1038/s41380-018-0344-6
Aslanoglou D, Bertera S, Sánchez-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.
pubmed: 33589583
pmcid: 7884786
doi: 10.1038/s41398-020-01171-z
Ipp E, Schusdziarra V, Harris V, Unger RH. Morphine-induced hyperglycemia: role of insulin and glucagon. Endocrinology 1980;107:461–3.
pubmed: 6993188
doi: 10.1210/endo-107-2-461
Green IC, Perrin D, Pedley KC, Leslie RD, Pyke DA. Effect of enkephalins and morphine on insulin secretion from isolated rat islets. Diabetologia 1980;19:158–61.
pubmed: 6998819
doi: 10.1007/BF00421864
Green IC, Ray K, Perrin D. Opioid peptide effects on insulin release and c-AMP in islets of Langerhans. Horm Metab Res. 1983;15:124–8.
pubmed: 6133828
doi: 10.1055/s-2007-1018648
Ahrén B, Lundquist I. Effects of naloxone on basal and stimulated insulin secretion in the mouse. Eur J Pharm. 1984;102:135–9.
doi: 10.1016/0014-2999(84)90346-7
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;74:1473–80.
pubmed: 6148357
pmcid: 425317
doi: 10.1172/JCI111560
van Loon GH, Appel NM. beta-Endorphin-induced hyperglycemia is mediated by increased central sympathetic outflow to adrenal medulla. Brain Res. 1981;204:236–41.
pubmed: 7248753
doi: 10.1016/0006-8993(81)90671-5
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;82:191–7.
pubmed: 8336863
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;18:615–23.
pubmed: 29937364
doi: 10.1016/j.pan.2018.06.006
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;888:217–24.
pubmed: 2874836
doi: 10.1016/0167-4889(86)90024-8
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.
Wilcox G. Insulin and insulin resistance. Clin Biochem Rev. 2005;26:19–39.
pubmed: 16278749
pmcid: 1204764
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;8:450–6.
pubmed: 15930973
doi: 10.1097/01.mco.0000172588.47811.63
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;18:1646–51.
doi: 10.1038/oby.2010.6
Cutler NR. Pharmacokinetic studies of antipsychotics in healthy volunteers versus patients. J Clin Psychiatry. 2001; 62 Suppl 5: 10–3; discussion 23–4.
Eli Lilly and Company. Zyprexa [package insert]. Indianapolis, IN: Eli Lilly and Company; 2018.
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;74:686–93.
pubmed: 28593216
pmcid: 5710250
doi: 10.1001/jamapsychiatry.2017.1322
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;22:560–73.
pubmed: 31263888
pmcid: 6754736
doi: 10.1093/ijnp/pyz037
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;195:245–51.
pubmed: 29158012
doi: 10.1016/j.schres.2017.10.014