Skip to main content
SpringerLink
Log in

Olanzapine/Samidorphan: A New Combination Treatment for Schizophrenia and Bipolar I Disorder Intended to Reduce Weight Gain

  • Review Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Olanzapine is a second-generation antipsychotic with established efficacy in several psychiatric disease states, but its use is limited because of weight gain and metabolic side effects. Samidorphan is a novel opioid antagonist that binds to mu-opioid, kappa-opioid, and delta-opioid receptors and is hypothesized to reduce cravings for high-calorie foods thus attenuating antipsychotic-induced weight gain. The combination product olanzapine/samidorphan was approved by the US Food and Drug Administration in June 2021 for the treatment of schizophrenia and bipolar I disorder; this article reviews the pharmacological properties of oral olanzapine/samidorphan and its clinical efficacy and tolerability with a focus on mitigation of olanzapine-induced weight gain in these patient populations. In clinical trials, the combination of olanzapine/samidorphan was associated with significantly less weight gain and smaller increases in waist circumference as compared with olanzapine monotherapy. Olanzapine/samidorphan demonstrated similar efficacy as olanzapine monotherapy and was well tolerated. Weight gain and metabolic side effects associated with olanzapine monotherapy can result in tolerability issues and potentially medication nonadherence. Olanzapine/samidorphan is an effective treatment for schizophrenia and bipolar I disorder with less weight gain than olanzapine monotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hirschfeld RMA, Bowden CL, Gitlin MJ, et al. Practice guideline for the treatment of patients with bipolar disorder. 2nd ed. Washington, DC: American Psychiatric Association; 2010. p. 82.

  2. American Psychiatric Association Practice. The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia. https://doi.org/10.1176/appi.books.9780890424841. Accessed 20 Sept 2021.

  3. Eli Lilly and Company. Olanzapine prescribing guide. 2006. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020592s042s043,021086s022s023,021253s026lbl.pdf. Accessed 26 Apr 2022.

  4. Haro JM, Suarez D, Novick D, et al. Three-year antipsychotic effectiveness in the outpatient care of schizophrenia: observational versus randomized studies results. Eur Neuropsychopharmacol. 2007;17(4):235–44. https://doi.org/10.1016/j.euroneuro.2006.09.005.

    Article  CAS  PubMed  Google Scholar 

  5. Lieberman JA, Rosenheck RA, Davis SM, Hsiao JK. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209–23.

    Article  CAS  Google Scholar 

  6. Kahn RS, Fleischhacker WW, Boter H, et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet. 2008;371(9618):1085–97. https://doi.org/10.1016/S0140-6736(08)60486-9.

    Article  CAS  PubMed  Google Scholar 

  7. Takahashi M, Nakahara N, Fujikoshi S, Iyo M. Remission, response, and relapse rates in patients with acute schizophrenia treated with olanzapine monotherapy or other atypical antipsychotic monotherapy: 12-month prospective observational study. Pragmat Obs Res. 2015;6:39–46. https://doi.org/10.2147/POR.S64973.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 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(04):498–503. https://doi.org/10.4088/JCP.10m06497.

    Article  CAS  PubMed  Google Scholar 

  9. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382(9896):951–62. https://doi.org/10.1016/S0140-6736(13)60733-3.

    Article  CAS  PubMed  Google Scholar 

  10. Chang S-C, Lu M-L. Metabolic and cardiovascular adverse effects associated with treatment with antipsychotic drugs. J Exp Clin Med. 2012;4(2):103–7. https://doi.org/10.1016/j.jecm.2012.01.007.

    Article  CAS  Google Scholar 

  11. Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 2010;36(1):71–93. https://doi.org/10.1093/schbul/sbp116.

    Article  PubMed  Google Scholar 

  12. World Health Organization. Premature death among people with severe mental disorders. https://www.who.int/mental_health/management/info_sheet.pdf. Accessed 20 Sept 2021.

  13. Alkermes, Inc.. Lybalvi (olanzapine and samidorphan) [prescribing information]. May 2021. Alkermes, Inc. https://www.lybalvi.com/lybalvi-prescribing-information.pdf. Accessed 26 Apr 2021.

  14. 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. https://doi.org/10.1016/j.schres.2017.10.014.

    Article  PubMed  Google Scholar 

  15. Deeks ED, Keating GM. Olanzapine/fluoxetine. Drugs. 2008;68(8):1115–37. https://doi.org/10.2165/00003495-200868080-00008.

    Article  CAS  PubMed  Google Scholar 

  16. Thomas K, Saadabadi A. Olanzapine. StatPearls. 2021. http://www.ncbi.nlm.nih.gov/books/NBK532903/. Accessed 8 Sept 2021.

  17. Lord CC, Wyler SC, Wan R, et al. The atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2C. J Clin Investig. 2021;127(9):3402–6. https://doi.org/10.1172/JCI93362.

    Article  Google Scholar 

  18. Czyzyk TA, Romero-Picó A, Pintar J, et al. Mice lacking δ-opioid receptors resist the development of diet-induced obesity. FASEB J. 2012;26(8):3483–92. https://doi.org/10.1096/fj.12-208041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Czyzyk TA, Nogueiras R, Lockwood JF, et al. κ-Opioid receptors control the metabolic response to a high-energy diet in mice. FASEB J. 2010;24(4):1151–9. https://doi.org/10.1096/fj.09-143610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. American Diabetes Association. Resistance to diet-induced obesity in μ-opioid receptor-deficient mice. https://diabetes.diabetesjournals.org/content/54/12/3510.long. Accessed 21 Sept 2021.

  21. Cunningham JI, Eyerman DJ, Todtenkopf MS, et al. Samidorphan mitigates olanzapine-induced weight gain and metabolic dysfunction in rats and non-human primates. J Psychopharmacol. 2019;33(10):1303–16. https://doi.org/10.1177/0269881119856850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shram MJ, Silverman B, Ehrich E, et al. Use of remifentanil in a novel clinical paradigm to characterize onset and duration of opioid blockade by samidorphan, a potent mu-receptor antagonsist. J Clin Psychopharmacol. 2015;35(3):242–9.

    Article  CAS  Google Scholar 

  23. Tabarin A, Diz-Chaves Y, Carmona MC, et al. Resistence to diet-induced obesity in mu-opioid receptor-deficient mice: evidence for a “thrifty gene.” Diabetes. 2005;54(12):3510–6.

    Article  CAS  Google Scholar 

  24. Sun L, Mills R, Sadler BM, Rege B. Population pharmacokinetics of olanzapine and samidorphan when administered in combination in healthy subjects and patients with schizophrenia. J Clin Pharmacol. 2021;61(11):1430–41.

    Article  CAS  Google Scholar 

  25. Sun L, McDonnell D, von Moltke L. Pharmacokinetics and short-term safety of ALKS 3831, a fixed-dose combination of olanazapine and samidorphan, in adult subjects with schizophrenia. Clin Ther. 2018;40(11):1845–54.

    Article  CAS  Google Scholar 

  26. Turncliff R, Dipetrillo L, Sliverman B, Ehrich E. Single- and multiple-dose pharmacokinetics of samidorphan, a novel opioid antagonist, in healthy volunteers. Clin Ther. 2015;37(2):338–48.

    Article  CAS  Google Scholar 

  27. Callaghan JT, Bergstrom RF, Ptak LR, Beasley CM. Olanzapine: pharmacokinetic and pharmacodynamic profile. Clin Pharmacokinet. 1999;37(3):177–93. https://doi.org/10.2165/00003088-199937030-00001.

    Article  CAS  PubMed  Google Scholar 

  28. Kumar V, Lu H, Hard M, von Moltke L. Characterization of the pharmacokinetics of samidorphan in healthy volunteers: absolute bioavailability and the effect of food and age. Drugs R D. 2019;19(3):277–87. https://doi.org/10.1007/s40268-019-00280-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sun L, von Moltke L, Yeo KR. Application of physiologically based pharmacokinetic modeling to predict the effect of renal impairment on the pharmacokinetics of olanzapine and samidorphan given in combination. Clin Pharmacokinet. 2021;60: 637647.

    Google Scholar 

  30. Sun L, von Moltke L, Yeo KR. Physiologically-based pharmacokinetic modeling for predicting drug interactions of a combination of olanzapine and samidorphan. CPT Pharmacomet Syst Pharmacol. 2020;9:106–14.

    Article  Google Scholar 

  31. NORC. One-third of Americans have received an opioid prescription in the past two years. https://www.norc.org/NewsEventsPublications/PressReleases/Pages/one-third-of-americans-have-received-an-opioid-prescription-in-the-past-two-years.aspx. Accessed 16 Sept 2021.

  32. Davis MA, Lin LA, Liu H, Sites BD. Prescription opioid use among adults with mental health disorders in the United States. J Am Board Fam Med. 2017;30(4):407–17. https://doi.org/10.3122/jabfm.2017.04.170112.

    Article  PubMed  Google Scholar 

  33. Martin WF, DiPetrillo L. 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(6):457–67.

    Article  Google Scholar 

  34. Potkin SG, Kunovac J, Silverman BL, et al. Efficacy and safety of a combination of olanzapine and samidorphan in adult patients with an acute exacerbation of schizophrenia: outcomes from the randomized, phase 3 ENLIGHTEN-1 study. J Clin Psychiatry. 2020. https://doi.org/10.4088/JCP.19m12769.

    Article  PubMed  Google Scholar 

  35. Correll CU, Newcomer JW, Silverman B, et al. Effects of olanzapine combined with samidorphan on weight gain in schizophrenia: a 24-week phase 3 study. AJP. 2020;177(12):1168–78. https://doi.org/10.1176/appi.ajp.2020.19121279.

    Article  Google Scholar 

  36. Kahn RS, Silverman BL, DiPetrillo L, et al. A phase 3, multicenter study to assess the 1-year safety and tolerability of a combination of olanzapine and samidorphan in patients with schizophrenia: results from the ENLIGHTEN-2 long-term extension. Schizophr Res. 2021;232:45–53. https://doi.org/10.1016/j.schres.2021.04.009.

    Article  PubMed  Google Scholar 

  37. ClinicalTrials.gov. https://www.clinicaltrials.gov/. Accessed 22 Mar 2022.

  38. Brunette MF, Correll CU, O’Malley SS, et al. Olanzapine plus samidorphan (ALKS 3831) in schizophrenia and comorbid alcohol use disorder: a phase 2, randomized clinical trial. J Clin Psychiatry. 2020. https://doi.org/10.4088/JCP.19m12786.

    Article  PubMed  Google Scholar 

  39. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) Study. JAMA. 1990;264(19):2511–8.

    Article  CAS  Google Scholar 

  40. Jónsdóttir H, Opjordsmoen S, Birkenaes AB, et al. Predictors of medication adherence in patients with schizophrenia and bipolar disorder. Acta Psychiatr Scand. 2013;127(1):23–33. https://doi.org/10.1111/j.1600-0447.2012.01911.x.

    Article  PubMed  Google Scholar 

  41. Jones RM, Lichtenstein P, Grann M, Långström N, Fazel S. Alcohol use disorders in schizophrenia: a national cohort study of 12,653 patients. J Clin Psychiatry. 2011;72(6):775–9. https://doi.org/10.4088/JCP.10m06320.

    Article  PubMed  Google Scholar 

  42. Hasan A, Falkai P, Wobrock T, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia: a short version for primary care. Int J Psychiatry Clin Pract. 2017;21(2):82–90. https://doi.org/10.1080/13651501.2017.1291839.

    Article  PubMed  Google Scholar 

  43. Green AI, Brunette MF, Dawson R, et al. Long-acting injectable vs oral risperidone for schizophrenia and co-occurring alcohol use disorder: a randomized trial. J Clin Psychiatry. 2015;76(10):1359–65. https://doi.org/10.4088/JCP.13m08838.

    Article  PubMed  Google Scholar 

  44. Petrakis IL, O’Malley S, Rounsaville B, et al. Naltrexone augmentation of neuroleptic treatment in alcohol abusing patients with schizophrenia. Psychopharmacology. 2004;174(2):300. https://doi.org/10.1007/s00213-004-1881-z.

    Article  CAS  Google Scholar 

  45. O’Malley SS, Todtenkopf MS, Du Y, et al. Effects of the opioid system modulator, samidorphan, on measures of alcohol consumption and patient-reported outcomes in adults with alcohol dependence. Alcohol Clin Exp Res. 2018;42(10):2011–21.

    Article  CAS  Google Scholar 

  46. ScienceDirect. Factors affecting smoking in schizophrenia. https://www.sciencedirect.com/science/article/abs/pii/S0010440X01155100?via%3Dihub. Accessed 15 Sept 2021.

  47. Carrillo JA, Herráiz AG, Ramos SI, Gervasini G, Vizcaíno S, Benítez J. Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol. 2003;23(2):119–27.

    Article  CAS  Google Scholar 

  48. ScienceDirect. Smoking and schizophrenia. https://www.sciencedirect.com/science/article/abs/pii/092099649290024Y?via%3Dihub. Accessed 15 Sept 2021.

  49. Tsuda Y, Saruwatari J, Yasui-Furukori N. Meta-analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine. BMJ Open. 2014;4(3): e004216. https://doi.org/10.1136/bmjopen-2013-004216.

    Article  PubMed  PubMed Central  Google Scholar 

  50. The Top 200 of 2019. https://clincalc.com/DrugStats/Top200Drugs.aspx. Accessed 29 Sept 2021.

  51. Mizuno Y, Suzuki T, Nakagawa A, Yoshida K, Mimura M, Fleischhacker WW, et al. Pharmacological strategies to counteractn antipsychotic-induced weight gain and metabolic adverse effects in schizophrenia: a systematic review and meta-analysis. Schizophr Bull. 2014;40(6):1385–402.

    Article  Google Scholar 

  52. de Silva VA, Suraweera C, Ratnatunga SS, Dayabandara M, Wanniarachchi N, Hanwella R. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry. 2016;16(1):341.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Pharmacy Practice and Administration, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO, 64108, USA

    Madeline M. Corrao & Leigh Anne Nelson

Authors
  1. Madeline M. Corrao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leigh Anne Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leigh Anne Nelson.

Ethics declarations

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Conflict of interest

The authors declaration of conflict of interest is as follows: Madeline M. Corrao has nothing to disclose. Leigh Anne Nelson served on an advisory board for Sunovion and Janssen pharmaceutical companies. She has received research funding from Boehringer Ingelheim, Alkermes, Inc. She is also a consultant in the speaker’s bureau of Alkermes Inc. for the following drugs: Aristada and Lybalvi. Alkermes, Inc. is the manufacturer of Lybalvi (olanzapine/samidorphan).

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent of publication

Not applicable.

Availability of data and material

Not applicable.

Code availability

Not applicable.

Authors’ contributions

Madeline M. Corrao conducted a literature analysis, wrote the paper, and completed revisions. Leigh Anne Nelson conceived the paper concept, conducted a literature analysis, edited the paper, submitted the paper, and is solely responsible for completing the revisions following peer review.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Corrao, M.M., Nelson, L.A. Olanzapine/Samidorphan: A New Combination Treatment for Schizophrenia and Bipolar I Disorder Intended to Reduce Weight Gain. CNS Drugs 36, 605–616 (2022). https://doi.org/10.1007/s40263-022-00923-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-022-00923-3

Search

Navigation