Combination Olanzapine and Samidorphan for the Management of Schizophrenia and Bipolar 1 Disorder in Adults: A Narrative Review
Schizophrenia is a debilitating psychotic disorder characterized by positive symptoms such as delusions, hallucinations, and disorganized thoughts, and negative symptoms like lack of effect or motivation. Bipolar 1 disorder (B1D) is a psychiatric illness characterized by recurrent manic episodes in alternation with depressive episodes and interspersed periods of euthymia, ultimately resulting in psychological distress and impairment of daily functioning. Effective treatments are needed for both schizophrenia and B1D to reach the treatment goals of reducing the debilitating symptomology, improving social functioning and quality of life, and increasing the chances of recovery and more favorable long-term outcomes. To date, olanzapine is one of the most efficacious atypical antipsychotics (AAPs) for the treatment of both schizophrenia and B1D and is associated with fewer extrapyramidal effects compared to other treatments. However, compared to other AAPs, olanzapine is associated with a greater chance of metabolic syndrome, limiting its clinical use and affecting treatment compliance. Samidorphan mitigates the weight gain side effects of olanzapine by antagonizing μ-, κ-, and δ-opioid receptors. The use of combination drugs to treat psychiatric conditions is an emerging field with the goal of increasing therapeutic efficacy and decreasing undesirable side effects. Clinical trials have demonstrated combination on olanzapine and samidorphan (OLZ/SAM) treatment resulted in significantly less weight gain than olanzapine monotherapy. Clinical trial patients reported improvements in symptoms of psychosis, reduced weight gain, and overall satisfaction with their treatment. OLZ/SAM has been as shown to be a safe and effective pharmaceutical option for the clinical management of schizophrenia and B1D.
1. Hany M, Rehman B, Azhar Y, Chapman J. Schizophrenia. In: StatPearls. StatPearls Publishing; 2021. Accessed September 15, 2021. http://www.ncbi.nlm.nih.gov/books/NBK539864/
2. Tandon R, Gaebel W, Barch DM, et al. Definition and description of schizophrenia in the DSM-5. Schizophr Res. 2013;150(1):3-10. doi:10.1016/j.schres.2013.05.028
3. Marder SR, Cannon TD. Schizophrenia. Ropper AH, ed. N Engl J Med. 2019;381(18):1753-1761. doi:10.1056/nejmra1808803
4. Chaiyakunapruk N, Chong HY, Teoh SL, Wu DBC, Kotirum S, Chiou CF. Global economic burden of schizophrenia: a systematic review. Neuropsychiatr Dis Treat. 2016;12:357-373. doi:10.2147/ndt.s96649
5. Carvalho AF, Firth J, Vieta E. Bipolar Disorder. Ropper AH, ed. N Engl J Med. 2020;383(1):58-66. doi:10.1056/nejmra1906193
6. Ironside ML, Johnson SL, Carver CS. Identity in bipolar disorder: self-worth and achievement. J Pers. 2020;88(1):45-58. doi:10.1111/jopy.12461
7. Freund N, Juckel G. Bipolar Disorder: Its Etiology and How to Model in Rodents. Methods Mol Biol. 2019;2011:61-77. doi:10.1007/978-1-4939-9554-7_4
8. Marangoni C, Faedda GL, Baldessarini RJ. Clinical and Environmental Risk Factors for Bipolar Disorder: Review of Prospective Studies. Harv Rev Psychiatry. 2018;26(1):1-7. doi:10.1097/hrp.0000000000000161
9. McIntyre RS, Berk M, Brietzke E, et al. Bipolar disorders. Lancet. 2020;396(10265):1841-1856. doi:10.1016/s0140-6736(20)31544-0
10. Bessonova L, Ogden K, Doane MJ, O'Sullivan AK, Tohen M. The Economic Burden of Bipolar Disorder in the United States: A Systematic Literature Review. ClinicoEconomics Outcomes Res. 2020;12:481-497. doi:10.2147/ceor.s259338
11. Crespo-Facorro B, Such P, Nylander AG, et al. The burden of disease in early schizophrenia-a systematic literature review. Curr Med Res Opin. 2021;37(1):109-121. doi:10.1080/03007995.2020.1841618
12. Paik J. Olanzapine/Samidorphan: First Approval. Drugs. 2021;81(12):1431-1436. doi:10.1007/s40265-021-01568-0
13. McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia-An Overview. JAMA Psychiatry. 2020;77(2):201-210. doi:10.1001/jamapsychiatry.2019.3360
14. Saha S, Chant D, Welham J, McGrath J. A systematic review of the prevalence of schizophrenia. PLoS Med. 2005;2(5):e141. doi:10.1371/journal.pmed.0020141
15. Charlson FJ, Ferrari AJ, Santomauro DF, et al. Global Epidemiology and Burden of Schizophrenia: Findings From the Global Burden of Disease Study 2016. Schizophr Bull. 2018;44(6):1195-1203. doi:10.1093/schbul/sby058
16. Messias EL, Chen CY, Eaton WW. Epidemiology of Schizophrenia: Review of Findings and Myths. Psychiatr Clin North Am. 2007;30(3):323-338. doi:10.1016/j.psc.2007.04.007
17. Misiak B, Stramecki F, Gaweda L, et al. Interactions Between Variation in Candidate Genes and Environmental Factors in the Etiology of Schizophrenia and Bipolar Disorder: a Systematic Review. Mol Neurobiol. 2018;55(6):5075-5100. doi:10.1007/s12035-017-0708-y
18. Cardno AG, Gottesman II. Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. Am J Med Genet. 2000;97(1):12-17. doi:10.1002/(sici)1096-8628(200021)97:1
19. Misiak B, Frydecka D, Rybakowski JK. Editorial: Endophenotypes for Schizophrenia and Mood Disorders: Implications from Genetic, Biochemical, Cognitive, Behavioral, and Neuroimaging Studies. Front Psychiatry. 2016;7. doi:10.3389/fpsyt.2016.00083
20. Chen L, Selvendra A, Stewart A, Castle D. Risk factors in early and late onset schizophrenia. Compr Psychiatry. 2018;80:155-162. doi:10.1016/j.comppsych.2017.09.009
21. Stilo SA, Murray RM. Non-Genetic Factors in Schizophrenia. Curr Psychiatry Rep. 2019;21(10):100. doi:10.1007/s11920-019-1091-3
22. Laursen TM, Nordentoft M, Mortensen PB. Excess early mortality in schizophrenia. Annu Rev Clin Psychol. 2014;10(1):425-448. doi:10.1146/annurev-cli npsy-032813-153657
23. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421-427. doi:10.1038/nature13595
24. Green MJ, Chia TY, Cairns MJ, et al. Catechol-O-methyltransferase(COMT) genotype moderates the effects of childhood trauma on cognition and symptoms in schizophrenia. J Psychiatr Res. 2014;49:43-50. doi:10.1016/j.jpsychires.2013.10.018
25. van Os J, Rutten BP, Poulton R. Gene-environment interactions in schizophrenia: review of epidemiological findings and future directions. Schizophr Bull. 2008;34(6):1066-1082. doi:10.1093/schbul/sbn117
26. Fusar-Poli P, Radua J, McGuire P, Borgwardt S. Neuroanatomical Maps of Psychosis Onset: Voxel-wise Meta-Analysis of Antipsychotic-Naive VBM Studies. Schizophr Bull. 2012;38(6):1297-1307. doi:10.1093/schbul/sbr134
27. Kambeitz J, Kambeitz-Ilankovic L, Cabral C, et al. Aberrant Functional Whole-Brain Network Architecture in Patients With Schizophrenia: A Meta-analysis. Schizophr Bull. 2016;42(suppl 1):S13-S21. doi:10.1093/schbul/sby174
28. Sui J, Pearlson GD, Du Y, et al. In Search of Multimodal Neuroimaging Biomarkers of Cognitive Deficits in Schizophrenia. Biol Psychiatry. 2015;78(11):794-804. doi:10.1016/j.biopsych.2015.02.017
29. Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: overview and treatment options. PT Peer-Rev J Formul Manag. 2014;39(9):638-645.
30. Lieberman JA, Girgis RR, Brucato G, et al. Hippocampal dysfunction in the pathophysiology of schizophrenia: a selective review and hypothesis for early detection and intervention. Mol Psychiatry. 2018;23(8):1764-1772. doi:10.1038/mp.2017.249
31. Vieta E, Berk M, Schulze TG, et al. Bipolar disorders. Nat Rev Dis Primers. 2018;4(1):18008. doi:10.1038/nrdp.2018.8
32. James SL, Abate D, Abate KH, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789-1858. doi:10.1016/s0140-6736(18)32279-7
33. Quidé Y, Tozzi L, Corcoran M, Cannon DM, Dauvermann MR. The Impact of Childhood Trauma on Developing Bipolar Disorder: Current Understanding and Ensuring Continued Progress. Neuropsychiatr Dis Treat. 2020;16:3095-3115. doi:10.2147/ndt.s285540
34. Michalak EE, Murray G, Young AH, Lam RW. Burden of bipolar depression: impact of disorder and medications on quality of life. CNS Drugs. 2008;22(5):389-406. doi:10.2165/00023210-200822050-00003
35. Suppes T, Leverich GS, Keck PE Jr, et al. The Stanley Foundation Bipolar Treatment Outcome Network. II. Demographics and illness characteristics of the first 261 patients. J Affect Disord. 2001;67(1-3):45-59. doi:10.1016/s0165-0327(01)00432-3
36. Trager C, Decker L, Waehrens EE, Knorr U, Miskowiak K, Vinberg M. Influences of patient informed cognitive complaints on activities of daily living in patients with bipolar disorder. An exploratory cross-sectional study. Psychiatry Res. 2017;249:268-274. doi:10.1016/j.psychres.2016.12.058
37. Marwaha S, Durrani A, Singh S. Employment outcomes in people with bipolar disorder: a systematic review. Acta Psychiatr Scand. 2013;128(3):179-193. doi:10.1111/acps.12087
38. Lima IMM, Peckham AD, Johnson SL. Cognitive deficits in bipolar disorders: Implications for emotion. Clin Psychol Rev. 2018;59:126-136. doi:10.1016/j.cpr.2017.11.006
39. Merikangas KR, Jin R, He JP, et al. Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative. Arch Gen Psychiatry. 2011;68(3):241. doi:10.1001/archgenpsychiatry.2011.12
40. Magioncalda P, Martino M. A unified model of the pathophysiology of bipolar disorder. Mol Psychiatry. 2021;27(1):41380-41021. doi:10.1038/s41380-021-01091-4
41. Savitz J, Drevets WC. Bipolar and major depressive disorder: neuroimaging the developmental-degenerative divide. Neurosci Biobehav Rev. 2009;33(5):699-771. doi:10.1016/j.neubiorev.2009.01.004
42. Mechawar N, Savitz J. Neuropathology of mood disorders: do we see the stigmata of inflammation? Transl Psychiatry. 2016;6(11):e946. doi:10.1038/tp.2016.212
43. Nikolaus S, Antke C, Miller HW. In vivo imaging of synaptic function in the central nervous system: II. Mental and affective disorders. Behav Brain Res. 2009;204(1):32-66. doi:10.1016/j.bbr.2009.06.009
44. Menon V. Large-scale brain networks and psychopathology: a unifying triple network model. Trends Cogn Sci. 2011;15(10):483-506. doi:10.1016/j.tics.2011.08.003
45. Northoff G, Hirjak D, Wolf RC, Magioncalda P, Martino M. All roads lead to the motor cortex: psychomotor mechanisms and their biochemical modulation in psychiatric disorders. Mol Psychiatry. 2021;26(1):92-102. doi:10.1038/s41380-020-0814-5
46. Martino M, Magioncalda P. Tracing the psychopathology of bipolar disorder to the functional architecture of intrinsic brain activity and its neurotransmitter modulation: a three-dimensional model. Mol Psychiatry. Published online January 7, 2021. doi:10.1038/s41380-020-00982-2
47. Sayana P, Colpo GD, Simores LR, et al. A systematic review of evidence for the role of inflammatory biomarkers in bipolar patients. J Psychiatr Res. 2017;92:160-182. doi:10.1016/j.jpsychires.2017.03.018
48. Fernandes BS, Steiner J, Molendijk ML, et al. C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3(12):1147-1156. doi:10.1016/s2215-0366(16)30370-4
49. Réus GZ, Fries GR, Stertz L, et al. The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders. Neuroscience. 2015;300:141-154. doi:10.1016/j.neuroscience.2015.05.018
50. Barbosa IG, Rocha NP, Assis F, et al. Monocyte and lymphocyte activation in bipolar disorder: a new piece in the puzzle of immune dysfunction in mood disorders. Int J Neuropsychopharmacol. 2014;18(1):pyu021. doi:10.1093/ijnp/pyu021
51. Breunis MN, Kupka RW, Nolen WA, et al. High numbers of circulating activated T cells and raised levels of serum IL-2 receptor in bipolar disorder. Biol Psychiatry. 2003;53(2):157-165. doi:10.1016/s0006-3223(02)01452-x
52. Tsai SY, Chen KP, Yang YY, et al. Activation of indices of cell-mediated immunity in bipolar mania. Biol Psychiatry. 1999;45(8):989-994. doi:10.1016/s0006-3223(98)00159-0
53. do Prado CH, Rizzo LB, Wieck A, et al. Reduced regulatory T cells are associated with higher levels of Th1/TH17 cytokines and activated MAPK in type 1 bipolar disorder. Psychoneuroendocrinology. 2013;38(5):667-676. doi:10.1016/j.psyneuen.2012.08.005
54. Brambilla P, Bellani M, Isola M, et al. Increased M1/decreased M2 signature and signs of Th1/Th2 shift in chronic patients with bipolar disorder, but not in those with schizophrenia. Transl Psychiatry. 2014;4(7):e406. doi:10.1038/tp.2014.46
55. Kohler O, Sylvia LG, Bowden CL, et al. White blood cell count correlates with mood symptom severity and specific mood symptoms in bipolar disorder. Aust NZJ Psychiatry. 2017;51(4):355-365. doi:10.1177/0004867416644508
56. Wu W, Zheng YL, Tian LP, et al. Circulating T lymphocyte subsets, cytokines, and immune checkpoint inhibitors in patients with bipolar II or major depression: a preliminary study. Sci Rep. 2017;7(1):40530. doi:10.1038/srep40530
57. Tsai SY, Chung KH, Chen PH. Levels of interleukin-6 and high-sensitivity C-reactive protein reflecting mania severity in bipolar disorder. Bipolar Disord. 2017;19(8):708-709. doi:10.1111/bdi.12570
58. Sexton CE, Mackay CE, Ebmeier KP. A systematic review of diffusion tensor imaging studies in affective disorders. Biol Psychiatry. 2009;66(9):814-823. doi:10.1016/j.biopsych.2009.05.024
59. Vederine FE, Wessa M, Leboyer M, Houenou J. A meta-analysis of whole-brain diffusion tensor imaging studies in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(8):1820-1826. doi:10.1016/j.pnpbp.2011.05.009
60. Nortje G, Stein DJ, Radua J, Mataix-Cols D, Horn N. Systematic review and voxel-based meta-analysis of diffusion tensor imaging studies in bipolar disorder. J Affect Disord. 2013;150(2):192-200. doi:10.1016/j.jad.2013.05.034
61. Wise T, Radua J, Nortje G, Cleare AJ, Young AH, Arnone D. Voxel-Based Meta-Analytical Evidence of Structural Disconnectivity in Major Depression and Bipolar Disorder. Biol Psychiatry. 2016;79(4):293-302. doi:10.1016/j.biopsych.2015.03.004
62. Heng S, Song AW, Sim K. White matter abnormalities in bipolar disorder: insights from diffusion tensor imaging studies. J Neural Transm. 2010;117(5):639-654. doi:10.1007/s00702-010-0368-9
63. Favre P, for the ENIGMA Bipolar Disorder Working Group, Pauling M, et al. Widespread white matter microstructural abnormalities in bipolar disorder: evidence from mega- and meta-analyses across 3033 individuals. Neuropsychopharmacol. 2019;44(13):2285-2293. doi:10.1038/s41386-019-0485-6
64. Yeo BTT, Krienen FM, Sepulcre J, et al. The organization of the human cerebral cortex estimated by intrinsic functional connectivity. J Neurophysiol. 2011;106(3):1125-1165. doi:10.1152/jn.00338.2011
65. Drevets WC, Savitz J, Trimble M. The subgenual anterior cingulate cortex in mood disorders. CNS Spectr. 2008;13(8):663-681. doi:10.1017/s1092852900013754
66. Pani L, Porcella A, Gessa GL. The role of stress in the pathophysiology of the dopaminergic system. Mol Psychiatry. 2000;5(1):14-21. doi:10.1038/sj.mp.4000589
67. Lanfumey L, Mongeau R, Cohen-Salmon C, Hamon M. Corticosteroid-serotonin interactions in the neurobiological mechanisms of stress-related disorders. Neurosci Biobehav Rev. 2008;32(6):1174-1184. doi:10.1016/j.neubiorev.2008.04.006
68. Martino M, Magioncalda P, Huang Z, et al. Contrasting variability patterns in the default mode and sensorimotor networks balance in bipolar depression and mania. Proc Natl Acad Sci USA. 2016;113(17):4824-4829. doi:10.1073/pnas.1517558113
69. Conio B, Martino M, Magioncalda P, et al. Opposite effects of dopamine and serotonin on resting-state networks: review and implications for psychiatric disorders. Mol Psychiatry. 2020;25(1):82-93. doi:10.1038/s41380-019-0406-4
70. Greene M, Yan T, Chang E, Hartry A, Touya M, Broder MS. Medication adherence and discontinuation of long-acting injectable versus oral antipsychotics in patients with schizophrenia or bipolar disorder. J Med Econ. 2018;21(2):127-134. doi:10.1080/13696998.2017.1379412
71. Kondej M, Stepnicki P, Kaczor AA. Multi-Target Approach for Drug Discovery against Schizophrenia. Int J Mol Sci. 2018;19(10):3105. doi:10.3390/ijms19103105
72. Girdler SJ, Confino JE, Woesner ME. Exercise as a Treatment for Schizophrenia: A Review. Psychopharmacol Bull. 2019;49(1):56-69.
73. Nucifora FC Jr, Woznica E, Lee BJ, Cascella N, Sawa A. Treatment resistant schizophrenia: Clinical, biological, and therapeutic perspectives. Neurobiol Dis. 2019;131:104257. doi:10.1016/j.nbd.2018.08.016
74. Stepnicki P, Kondej M, Kaczor AA. Current Concepts and Treatments of Schizophrenia. Mol Basel Switz. 2018;23(8):2087. doi:10.3390/molecules23082087
75. Lau CI, Wang HC, Hsu JL, Liu ME. Does the dopamine hypothesis explain schizophrenia? Rev Neurosci. 2013;24(4):389-400. doi:10.1515/revneuro-2013-0011
76. Carlsson A, Lindqvist M. Effect of Chlorpromazine or Haloperidol on Formation of 3-Methoxytyramine and Normetanephrine in Mouse Brain. Acta Pharmacol Toxicol (Copenh). 2009;20(2):140-144. doi:10.1111/j.1600-0773.1963.tb01730.x
77. Moller HJ. Risperidone: a review. Expert Opin Pharmacother. 2005;6(5):803-818. doi:10.1517/14656566.6.5.803
78. Shapiro DA, Renock S, Arrington E, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacol. 2003;28(8):1400-1411. doi:10.1038/sj.npp.1300203
79. Pajonk FG, Wobrock T, Gruber O, et al. Hippocampal Plasticity in Response to Exercise in Schizophrenia. Arch Gen Psychiatry. 2010;67(2):133-143. doi:10.1001/archgenpsychiatry.2009.193
80. Cade JFJ. Lithium salts in the treatment of psychotic excitement. Aust NZ J Psychiatry. 1999;33(5):349-352. doi:10.1080/j.1440-1614.1999.06241.x
81. Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378(9799):1306-1315. doi:10.1016/s0140-6736(11)60873-8
82. Baldessarini RJ, Tondo L, Vázquez GH. Pharmacological treatment of adult bipolar disorder. Mol Psychiatry. 2019;24(2):198-217. doi:10.1038/s41380-018-0044-2
83. Yildiz A, Vieta E, Leucht S, Baldessarini RJ. Efficacy of Antimanic Treatments: Meta-analysis of Randomized, Controlled Trials. Neuropsychopharmacol. 2011;36(2):375-389. doi:10.1038/npp.2010.192
84. Baldessarini RJ, Salvatore P, Khalsa HMK, et al. Morbidity in 303 first-episode bipolar I disorder patients. Bipolar Disord. 2010;12(3):264-270. doi:10.1111/j.1399-5618.2010.00812.x
85. Forte A, Baldessarini RJ, Tondo L, Vazquez GH, Pompili M, Girardi P. Long-term morbidity in bipolar-I, bipolar-II, and unipolar major depressive disorders. JAffect Disord. 2015;178:71-78. doi:10.1016/j.jad.2015.02.011
86. Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders. Am J Psychiatry. 2013;170(11):1249-1262. doi:10.1176/appi.ajp.2013.13020185
87. Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition. Recommendations from the British Association for Psychopharmacology. J Psychopharmacol Oxf Engl. 2016;30(6):495-553. doi:10.1177/0269881116636545
88. Guzzetta F, Tondo L, Centorrino F, Baldessarini RJ. Lithium treatment reduces suicide risk in recurrent major depressive disorder. J Clin Psychiatry. 2007;68(03):380-383. doi:10.4088/jcp.v68n0304
89. Terao T, Ishida A, Kimura T, Yarita M, Hara T. Preventive Effects of Lamotrigine in Bipolar II Versus Bipolar I Disorder. J Clin Psychiatry. 2017;78(8):e1000-e1005. doi:10.4088/jcp.16m11404
90. Gold AK, Ornelas AC, Cirillo P, et al. Clinical applications of transcranial magnetic stimulation in bipolar disorder. Brain Behav. 2019;9(10):e01419. doi:10.1002/brb3.1419
91. Alkermes Announces FDA Approval of LYBALVITM for the Treatment of Schizophrenia and Bipolar I Disorder | BioSpace. Accessed September 7, 2021. https://www.biospace.com/article/releases/alke rmes-announces-fda-approval-of-lybalvi-for-the-trea tment-of-schizophrenia-and-bipolar-i-disorder/
92. Sun L, McDonnell D, Liu J, von Moltke L. Effect of Food on the Pharmacokinetics of a Combination of Olanzapine and Samidorphan. Clin Pharmacol Drug Dev. 2019;8(4):503-510. doi:10.1002/cpdd.688
93. Citrome L, Holt RIG, Walker DJ, Hoffmann VP. Weight gain and changes in metabolic variables following olanzapine treatment in schizophrenia and bipolar disorder. Clin Drug Investig. 2011;31(7):455-482. doi:10.2165/11589060-000000000-00000
94. Cunningham JI, Eyerman DJ, Tottenkopf MS, et al. Samidorphan mitigates olanzapine-induced weight gain and metabolic dysfunction in rats and non-human primates. J Psychopharmacol Oxf Engl. 2019;33(10):1303-1316. doi:10.1177/0269881119856850
95. Buchanan RW. How Much of an Advance Is the Addition of Samidorphan to Olanzapine? Am J Psychiatry. 2020;177(12):1113-1114. doi:10.1176/appi.ajp.2020.20091425
96. Lord CC, Wyler SC, Wan R, et al. The atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2C. J Clin Invest. 2017;127(9):3402-3406. doi:10.1172/jci93362
97. Effects of Olanzapine and Haloperidol on the Metabolic Status of Healthy Men. J Clin Endocrinol Metab. 2010;95(1). doi:10.1210/jc.2008-1815
98. 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;195:245-251. doi:10.1016/j.schres.2017.10.014
99. Martin WF, Correll CU, Weiden PJ, 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(6):457-467. doi:10.1176/appi.ajp.2018.18030280
100. Prescribing information for LYBALVI. Accessed September 7, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213378s000lbl.pdf
101. Thomas K, Saadabadi A. Olanzapine. In: StatPearls. StatPearls Publishing; 2021. Accessed September 7, 2021. http://www.ncbi.nlm.nih.gov/books/NBK532903/
102. Del Fabro L, Delvecchio G, D’Agostino A, Brambilla P. Effects of olanzapine during cognitive and emotional processing in schizophrenia: A review of functional magnetic resonance imaging findings. Hum Psychopharmacol Clin Exp. 2019;34(3):e2693. doi:10.1002/hup.2693
103. Chaudhary AMD, Khan MF, Dhillon SS, Naveed S. A Review of Samidorphan: A Novel Opioid Antagonist. Cureus. 2019;11(7):e5139. doi:10.7759/cureus.5139
104. Cunningham JI, Todtenkopf MS, Dean RL, et al. Samidorphan, an opioid receptor antagonist, attenuates drug-induced increases in extracellular dopamine concentrations and drug self-administration in male Wistar rats. Pharmacol Biochem Behav. 2021;204:173157. doi:10.1016/j.pbb.2021.173157
105. Smith KL, Cunningham JI, Eyerman DJ, Dean RL III, Deaver DR, Sanchez C. Opioid system modulators buprenorphine and samidorphan alter behavior and extracellular neurotransmitter concentrations in the Wistar Kyoto rat. Neuropharmacology. 2019;146:316-326. doi:10.1016/j.neuropharm.2018.11.015
106. Sun L, McDonnell D, von Moltke L. Pharmacokinetics and Short-term Safety of ALKS 3831, a Fixed-dose Combination of Olanzapine and Samidorphan, in Adult Subjects with Schizophrenia. Clin Ther. 2018;40(11):1845-1854.e2. doi:10.1016/j.clinthera.2018.09.002
107. Sun L, von Moltke L, Rowland Yeo K. Physiologically-Based Pharmacokinetic Modeling for Predicting Drug Interactions of a Combination of Olanzapine and Samidorphan. CPT Pharmacomet Syst Pharmacol. 2020;9(2):106-114. doi:10.1002/psp4.12488
108. Lowe EJ, Ackman ML. Impact of tobacco smoking cessation on stable clozapine or olanzapine treatment. Ann Pharmacother. 2010;44(4):727-732. doi:10.1345/aph.1m398
109. 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):1430-1441. doi:10.1002/jcph.1911
110. Sun L, Yagoda S, Du Y, von Moltke L. Effect of hepatic and renal impairment on the pharmacokinetics of olanzapine and samidorphan given in combination as a bilayer tablet. Drug Des Devel Ther. 2019;13:2941-2955. doi:10.2147/dddt.s2050000
111. Citrome L, Graham C, Simmons A, et al. A Combination of Olanzapine and Samidorphan in Adults with Schizophrenia and Bipolar I Disorder: Overview of Clinical Data. CNS Spectr. 2021;26(2):170-170. doi:10.1017/s1092852920002771
112. 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;81(2):19m12769. doi:10.4088/jcp.19m12769
113. Simmons A, Carpenter-Conlin J, Bessonova L, et al. Qualitative Clinical Trial Exit Interviews Evaluating Treatment Benefit, Burden, and Satisfaction in Patients with Schizophrenia. CNS Spectr. 2021;26(2):156-157. doi:10.1017/s1092852920002503
114. Yagoda S, Graham C, Simmons A, Arevalo C, Jiang Y, McDonnell D. Long-term safety and durability of effect with a combination of olanzapine and samidorphan in patients with schizophrenia: results from a 1-year open-label extension study. CNS Spectr. 2021;26(4):383-392. doi:10.1017/s1092852920001376
115. Srisurapanont M, Suttajit S, Likhitsathian S, Maneeton B, Maneeton N. A meta-analysis comparing short-term weight and cardiometabolic changes between olanzapine/samidorphan and olanzapine. Sci Rep. 2021;11(1):7583. doi:10.1038/s41598-021-87285-w
116. 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. Am J Psychiatry. 2020;177(12):1168-1178. doi:10.1176/appi.ajp.2020.19121279
117. 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. doi:10.1016/j.schres.2021.04.009
118. Kahn R, Silverman B, DiPetrillo L, et al. Phase 3 Safety and Tolerability Results of the Combination Olanzapine and Samidorphan in Patients with Schizophrenia: The 1 Year ENLIGHTEN-2-Extension. CNS Spectr. 2021;26(2):155-156. doi:10.1017/s1092852920002485
119. Sun L, McDonnell D, Liu J, von Moltke L. Bioequivalence of Olanzapine Given in Combination With Samidorphan as a Bilayer Tablet (ALKS 3831) Compared With Olanzapine-Alone Tablets: Results From a Randomized, Crossover Relative Bioavailability Study. Clin Pharmacol Drug Dev. 2019;8(4):459-466. doi:10.1002/cpdd.601
120. Sun L, Yagoda S, Yao B, Graham C, von Moltke L. Combination of Olanzapine and Samidorphan Has No Clinically Significant Effect on the Pharmacokinetics of Lithium or Valproate. Clin Drug Investig. 2020;40(1):55-64. doi:10.1007/s40261-019-00860-y
121. Sun L, Yagoda S, Xue H, et al. Combination of olanzapine and samidorphan has no clinically relevant effects on ECG parameters, including the QTc interval: results from a phase 1 QT/QTc study. Prog Neuropsychopharmacol Biol Psychiatry. 2020;100:109881. doi:10.1016/j.pnpbp.2020.109881
122. 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;81(2):19m12786. doi:10.4088/jcp.19m12786