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Orexin Receptor Antagonists as Emerging Treatments for Psychiatric Disorders

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Abstract

Orexins comprise two neuropeptides produced by orexin neurons in the lateral hypothalamus and are released by extensive projections of these neurons throughout the central nervous system. Orexins bind and activate their associated G protein-coupled orexin type 1 receptors (OX1Rs) and OX2Rs and act on numerous physiological processes, such as sleep-wake regulation, feeding, reward, emotion, and motivation. Research on the development of orexin receptor antagonists has dramatically increased with the approval of suvorexant for the treatment of primary insomnia. In the present review, we discuss recent findings on the involvement of the orexin system in the pathophysiology of psychiatric disorders, including sleep disorders, depression, anxiety, and drug addiction. We discuss the actions of orexin receptor antagonists, including selective OX1R antagonists (SORA1s), selective OX2R antagonists (SORA2s), and dual OX1/2R antagonists (DORAs), in the treatment of these disorders based on both preclinical and clinical evidence. SORA2s and DORAs have more pronounced efficacy in the treatment of sleep disorders, whereas SORA1s may be promising for the treatment of anxiety and drug addiction. We also discuss potential challenges and opportunities for the application of orexin receptor antagonists to clinical interventions.

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References

  1. de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 1998, 95: 322–327.

    PubMed  PubMed Central  Google Scholar 

  2. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998, 92: 573–585.

    CAS  PubMed  Google Scholar 

  3. Lee MG, Hassani OK, Jones BE. Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J Neurosci 2005, 25: 6716–6720.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Matsuki T, Sakurai T. Orexins and orexin receptors: from molecules to integrative physiology. Results Probl Cell Differ 2008, 46: 27–55.

    CAS  PubMed  Google Scholar 

  5. Boss C, Roch C. Recent trends in orexin research–2010 to 2015. Bioorg Med Chem Lett 2015, 25: 2875–2887.

    CAS  PubMed  Google Scholar 

  6. Nevarez N, de Lecea L. Recent advances in understanding the roles of hypocretin/orexin in arousal, affect, and motivation. F1000Res 2018, 7: F1000 Faculty Rev-1421.

  7. Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 2001, 435: 6–25.

    CAS  PubMed  Google Scholar 

  8. Bisetti A, Cvetkovic V, Serafin M, Bayer L, Machard D, Jones BE, et al. Excitatory action of hypocretin/orexin on neurons of the central medial amygdala. Neuroscience 2006, 142: 999–1004.

    CAS  PubMed  Google Scholar 

  9. Sakurai T. The role of orexin in motivated behaviours. Nat Rev Neurosci 2014, 15: 719–731.

    CAS  PubMed  Google Scholar 

  10. Flores A, Saravia R, Maldonado R, Berrendero F. Orexins and fear: implications for the treatment of anxiety disorders. Trends Neurosci 2015, 38: 550–559.

    CAS  PubMed  Google Scholar 

  11. Mahoney CE, Cogswell A, Koralnik IJ, Scammell TE. The neurobiological basis of narcolepsy. Nat Rev Neurosci 2019, 20: 83–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Klockars A, Levine AS, Olszewski PK. Hypothalamic integration of the endocrine signaling related to food intake. Curr Top Behav Neurosci 2018. https://doi.org/10.1007/7854_2018_54.

    Article  Google Scholar 

  13. Hirasawa M, Parsons MP, Alberto CO. Interaction between orexins and the mesolimbic system for overriding satiety. Rev Neurosci 2007, 18: 383–393.

    PubMed  Google Scholar 

  14. Morello G, Imperatore R, Palomba L, Finelli C, Labruna G, Pasanisi F, et al. Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling. Proc Natl Acad Sci U S A 2016, 113: 4759–4764.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Williams DL. Neural integration of satiation and food reward: role of GLP-1 and orexin pathways. Physiol Behav 2014, 136: 194–199.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Cun Y, Tang L, Yan J, He C, Li Y, Hu Z, et al. Orexin A attenuates the sleep-promoting effect of adenosine in the lateral hypothalamus of rats. Neurosci Bull 2014, 30: 877–886.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, de Lecea L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 2007, 450: 420–424.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Dugovic C, Shelton JE, Yun S, Bonaventure P, Shireman BT, Lovenberg TW. Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism. Front Neurosci 2014, 8: 28.

    PubMed  PubMed Central  Google Scholar 

  19. Mieda M, Hasegawa E, Kisanuki YY, Sinton CM, Yanagisawa M, Sakurai T. Differential roles of orexin receptor-1 and -2 in the regulation of non-REM and REM sleep. J Neurosci 2011, 31: 6518–6526.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. James MH, Campbell EJ, Dayas CV. Role of the orexin/hypocretin system in stress-related psychiatric disorders. Curr Top Behav Neurosci 2017, 33: 197–219.

    CAS  PubMed  Google Scholar 

  21. Baimel C, Bartlett SE, Chiou LC, Lawrence AJ, Muschamp JW, Patkar O, et al. Orexin/hypocretin role in reward: implications for opioid and other addictions. Br J Pharmacol 2015, 172: 334–348.

    CAS  PubMed  Google Scholar 

  22. Boss C, Roch C. Orexin research: patent news from 2016. Expert Opin Ther Pat 2017, 27: 1123–1133.

    CAS  PubMed  Google Scholar 

  23. Coleman PJ, Gotter AL, Herring WJ, Winrow CJ, Renger JJ. The discovery of suvorexant, the first orexin receptor drug for insomnia. Annu Rev Pharmacol Toxicol 2017, 57: 509–533.

    CAS  PubMed  Google Scholar 

  24. Kuriyama A, Tabata H. Suvorexant for the treatment of primary insomnia: a systematic review and meta-analysis. Sleep Med Rev 2017, 35: 1–7.

    PubMed  Google Scholar 

  25. Sheridan C. Insomniacs get new mechanism sleep drug Belsomra. Nat Biotechnol 2014, 32: 968.

    CAS  PubMed  Google Scholar 

  26. Murphy P, Moline M, Mayleben D, Rosenberg R, Zammit G, Pinner K, et al. Lemborexant, a dual orexin receptor antagonist (DORA) for the treatment of insomnia disorder: results from a bayesian, adaptive, randomized, double-blind, placebo-controlled study. J Clin Sleep Med 2017, 13: 1289–1299.

    PubMed  PubMed Central  Google Scholar 

  27. Yeoh JW, Campbell EJ, James MH, Graham BA, Dayas CV. Orexin antagonists for neuropsychiatric disease: progress and potential pitfalls. Front Neurosci 2014, 8: 36.

    PubMed  PubMed Central  Google Scholar 

  28. Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron 2017, 93: 747–765.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang XY, Yu L, Zhuang QX, Zhu JN, Wang JJ. Central functions of the orexinergic system. Neurosci Bull 2013, 29: 355–365.

    PubMed  PubMed Central  Google Scholar 

  30. Flores A, Maldonado R, Berrendero F. Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far. Front Neurosci 2013, 7: 256.

    PubMed  PubMed Central  Google Scholar 

  31. Sakurai T, Mieda M. Connectomics of orexin-producing neurons: interface of systems of emotion, energy homeostasis and arousal. Trends Pharmacol Sci 2011, 32: 451–462.

    CAS  PubMed  Google Scholar 

  32. Sargin D. The role of the orexin system in stress response. Neuropharmacology 2019, 154: 68–78.

    CAS  PubMed  Google Scholar 

  33. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999, 98: 365–376.

    CAS  PubMed  Google Scholar 

  34. Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000, 27: 469–474.

    CAS  PubMed  Google Scholar 

  35. Takenoshita S, Sakai N, Chiba Y, Matsumura M, Yamaguchi M, Nishino S. An overview of hypocretin based therapy in narcolepsy. Expert Opin Investig Drugs 2018, 27: 389–406.

    CAS  PubMed  Google Scholar 

  36. Nepovimova E, Janockova J, Misik J, Kubik S, Stuchlik A, Vales K, et al. Orexin supplementation in narcolepsy treatment: a review. Med Res Rev 2019, 39: 961–975.

    CAS  PubMed  Google Scholar 

  37. Irukayama-Tomobe Y, Ogawa Y, Tominaga H, Ishikawa Y, Hosokawa N, Ambai S, et al. Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models. Proc Natl Acad Sci U S A 2017, 114: 5731–5736.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Summers CH, Yaeger JDW, Staton CD, Arendt DH, Summers TR. Orexin/hypocretin receptor modulation of anxiolytic and antidepressive responses during social stress and decision-making: potential for therapy. Brain Res 2018; e-pub ahead of print 24 December 2018; https://doi.org/10.1016/j.brainres.2018.12.036.

  39. Staton CD, Yaeger JDW, Khalid D, Haroun F, Fernandez BS, Fernandez JS, et al. Orexin 2 receptor stimulation enhances resilience, while orexin 2 inhibition promotes susceptibility, to social stress, anxiety and depression. Neuropharmacology 2018, 143: 79–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Betschart C, Hintermann S, Behnke D, Cotesta S, Fendt M, Gee CE, et al. Identification of a novel series of orexin receptor antagonists with a distinct effect on sleep architecture for the treatment of insomnia. J Med Chem 2013, 56: 7590–7607.

    CAS  PubMed  Google Scholar 

  41. Etori K, Saito YC, Tsujino N, Sakurai T. Effects of a newly developed potent orexin-2 receptor-selective antagonist, compound 1 m, on sleep/wakefulness states in mice. Front Neurosci 2014, 8: 8.

    PubMed  PubMed Central  Google Scholar 

  42. Gotter AL, Forman MS, Harrell CM, Stevens J, Svetnik V, Yee KL, et al. Orexin 2 receptor antagonism is sufficient to promote NREM and REM sleep from mouse to man. Sci Rep 2016, 6: 27147.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Mang GM, Durst T, Burki H, Imobersteg S, Abramowski D, Schuepbach E, et al. The dual orexin receptor antagonist almorexant induces sleep and decreases orexin-induced locomotion by blocking orexin 2 receptors. Sleep 2012, 35: 1625–1635.

    PubMed  PubMed Central  Google Scholar 

  44. Chen L, McKenna JT, Bolortuya Y, Winston S, Thakkar MM, Basheer R, et al. Knockdown of orexin type 1 receptor in rat locus coeruleus increases REM sleep during the dark period. Eur J Neurosci 2010, 32: 1528–1536.

    PubMed  PubMed Central  Google Scholar 

  45. Bonaventure P, Dugovic C, Shireman B, Preville C, Yun S, Lord B, et al. Evaluation of JNJ-54717793 a novel brain penetrant selective orexin 1 receptor antagonist in two rat models of panic attack provocation. Front Pharmacol 2017, 8: 357.

    PubMed  PubMed Central  Google Scholar 

  46. Dugovic C, Shelton JE, Aluisio LE, Fraser IC, Jiang X, Sutton SW, et al. Blockade of orexin-1 receptors attenuates orexin-2 receptor antagonism-induced sleep promotion in the rat. J Pharmacol Exp Ther 2009, 330: 142–151.

    CAS  PubMed  Google Scholar 

  47. Winrow CJ, Gotter AL, Cox CD, Doran SM, Tannenbaum PL, Breslin MJ, et al. Promotion of sleep by suvorexant-a novel dual orexin receptor antagonist. J Neurogenet 2011, 25: 52–61.

    CAS  PubMed  Google Scholar 

  48. Hoyer D, Durst T, Fendt M, Jacobson LH, Betschart C, Hintermann S, et al. Distinct effects of IPSU and suvorexant on mouse sleep architecture. Front Neurosci 2013, 7: 235.

    PubMed  PubMed Central  Google Scholar 

  49. Tsuneki H, Kon K, Ito H, Yamazaki M, Takahara S, Toyooka N, et al. Timed inhibition of orexin system by suvorexant improved sleep and glucose metabolism in type 2 diabetic db/db mice. Endocrinology 2016, 157: 4146–4157.

    CAS  PubMed  Google Scholar 

  50. Li SB, Nevarez N, Giardino WJ, de Lecea L. Optical probing of orexin/hypocretin receptor antagonists. Sleep 2018. https://doi.org/10.1093/sleep/zsy141.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Parks GS, Warrier DR, Dittrich L, Schwartz MD, Palmerston JB, Neylan TC, et al. The dual hypocretin receptor antagonist almorexant is permissive for activation of wake-promoting systems. Neuropsychopharmacology 2016, 41: 1144–1155.

    CAS  PubMed  Google Scholar 

  52. Citrome L. Suvorexant for insomnia: a systematic review of the efficacy and safety profile for this newly approved hypnotic - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract 2014, 68: 1429–1441.

    CAS  PubMed  Google Scholar 

  53. Kishi T, Matsunaga S, Iwata N. Suvorexant for primary insomnia: a systematic review and meta-analysis of randomized placebo-controlled trials. PLoS One 2015, 10: e0136910.

    PubMed  PubMed Central  Google Scholar 

  54. Lee-Iannotti JK, Parish JM. Suvorexant: a promising, novel treatment for insomnia. Neuropsychiatr Dis Treat 2016, 12: 491–495.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Norman JL, Anderson SL. Novel class of medications, orexin receptor antagonists, in the treatment of insomnia – critical appraisal of suvorexant. Nat Sci Sleep 2016, 8: 239–247.

    PubMed  PubMed Central  Google Scholar 

  56. Herring WJ, Connor KM, Snyder E, Snavely DB, Zhang Y, Hutzelmann J, et al. Suvorexant in elderly patients with insomnia: pooled analyses of data from phase III randomized controlled clinical trials. Am J Geriatr Psychiatry 2017, 25: 791–802.

    PubMed  Google Scholar 

  57. Herring WJ, Connor KM, Ivgy-May N, Snyder E, Liu K, Snavely DB, et al. Suvorexant in patients with insomnia: results from two 3-month randomized controlled clinical trials. Biol Psychiatry 2016, 79: 136–148.

    CAS  PubMed  Google Scholar 

  58. Herring WJ, Connor KM, Snyder E, Snavely DB, Zhang Y, Hutzelmann J, et al. Suvorexant in patients with insomnia: pooled analyses of three-month data from phase-3 randomized controlled clinical trials. J Clin Sleep Med 2016, 12: 1215–1225.

    PubMed  PubMed Central  Google Scholar 

  59. Herring WJ, Connor KM, Snyder E, Snavely DB, Zhang Y, Hutzelmann J, et al. Clinical profile of suvorexant for the treatment of insomnia over 3 months in women and men: subgroup analysis of pooled phase-3 data. Psychopharmacology (Berl) 2017, 234: 1703–1711.

    CAS  Google Scholar 

  60. Sun H, Kennedy WP, Wilbraham D, Lewis N, Calder N, Li X, et al. Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men. Sleep 2013, 36: 259–267.

    PubMed  PubMed Central  Google Scholar 

  61. Connor KM, Mahoney E, Jackson S, Hutzelmann J, Zhao X, Jia N, et al. A phase II dose-ranging study evaluating the efficacy and safety of the orexin receptor antagonist filorexant (MK-6096) in patients with primary insomnia. Int J Neuropsychopharmacol 2016, 19: pyw022.

    PubMed  PubMed Central  Google Scholar 

  62. Kawabe K, Horiuchi F, Ochi M, Nishimoto K, Ueno SI, Oka Y. Suvorexant for the treatment of insomnia in adolescents. J Child Adolesc Psychopharmacol 2017, 27: 792–795.

    CAS  PubMed  Google Scholar 

  63. Herring WJ, Connor KM, Snyder E, Snavely DB, Morin CM, Lines C, et al. Effects of suvorexant on the Insomnia Severity Index in patients with insomnia: analysis of pooled phase 3 data. Sleep Med 2019, 56: 219–223.

    PubMed  Google Scholar 

  64. Michelson D, Snyder E, Paradis E, Chengan-Liu M, Snavely DB, Hutzelmann J, et al. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014, 13: 461–471.

    CAS  PubMed  Google Scholar 

  65. Ma J, Svetnik V, Snyder E, Lines C, Roth T, Herring WJ. Electroencephalographic power spectral density profile of the orexin receptor antagonist suvorexant in patients with primary insomnia and healthy subjects. Sleep 2014, 37: 1609–1619.

    PubMed  PubMed Central  Google Scholar 

  66. Snyder E, Ma J, Svetnik V, Connor KM, Lines C, Michelson D, et al. Effects of suvorexant on sleep architecture and power spectral profile in patients with insomnia: analysis of pooled phase 3 data. Sleep Med 2016, 19: 93–100.

    PubMed  Google Scholar 

  67. Bettica P, Squassante L, Groeger JA, Gennery B, Winsky-Sommerer R, Dijk DJ. Differential effects of a dual orexin receptor antagonist (SB-649868) and zolpidem on sleep initiation and consolidation, SWS, REM sleep, and EEG power spectra in a model of situational insomnia. Neuropsychopharmacology 2012, 37: 1224–1233.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Bettica P, Squassante L, Zamuner S, Nucci G, Danker-Hopfe H, Ratti E. The orexin antagonist SB-649868 promotes and maintains sleep in men with primary insomnia. Sleep 2012, 35: 1097–1104.

    PubMed  PubMed Central  Google Scholar 

  69. Hamuro A, Honda M, Wakaura Y. Suvorexant for the treatment of insomnia in patients with Alzheimer’s disease. Aust N Z J Psychiatry 2018, 52: 207–208.

    PubMed  Google Scholar 

  70. Toi N, Inaba M, Kurajoh M, Morioka T, Hayashi N, Hirota T, et al. Improvement of glycemic control by treatment for insomnia with suvorexant in type 2 diabetes mellitus. J Clin Transl Endocrinol 2019, 15: 37–44.

    PubMed  Google Scholar 

  71. Kawada K, Ohta T, Tanaka K, Miyamura M, Tanaka S. Addition of suvorexant to ramelteon therapy for improved sleep quality with reduced delirium risk in acute stroke patients. J Stroke Cerebrovasc Dis 2019, 28: 142–148.

    PubMed  Google Scholar 

  72. Suzuki H, Hibino H, Inoue Y, Mikami A, Matsumoto H, Mikami K. Reduced insomnia following short-term administration of suvorexant during aripiprazole once-monthly treatment in a patient with schizophrenia. Asian J Psychiatr 2017, 28: 165–166.

    PubMed  Google Scholar 

  73. Tabata H, Kuriyama A, Yamao F, Kitaguchi H, Shindo K. Suvorexant-induced dream enactment behavior in parkinson disease: a case report. J Clin Sleep Med 2017, 13: 759–760.

    PubMed  PubMed Central  Google Scholar 

  74. Uemura N, McCrea J, Sun H, Donikyan M, Zammit G, Liu R, et al. Effects of the orexin receptor antagonist suvorexant on respiration during sleep in healthy subjects. J Clin Pharmacol 2015, 55: 1093–1100.

    CAS  PubMed  Google Scholar 

  75. Sun H, Palcza J, Card D, Gipson A, Rosenberg R, Kryger M, et al. Effects of suvorexant, an orexin receptor antagonist, on respiration during sleep in patients with obstructive sleep apnea. J Clin Sleep Med 2016, 12: 9–17.

    PubMed  PubMed Central  Google Scholar 

  76. Sun H, Palcza J, Rosenberg R, Kryger M, Siringhaus T, Rowe J, et al. Effects of suvorexant, an orexin receptor antagonist, on breathing during sleep in patients with chronic obstructive pulmonary disease. Respir Med 2015, 109: 416–426.

    PubMed  Google Scholar 

  77. Brooks S, Jacobs GE, de Boer P, Kent JM, Van Nueten L, van Amerongen G, et al. The selective orexin-2 receptor antagonist seltorexant improves sleep: An exploratory double-blind, placebo controlled, crossover study in antidepressant-treated major depressive disorder patients with persistent insomnia. J Psychopharmacol 2019, 33: 202–209.

    CAS  PubMed  Google Scholar 

  78. De Boer P, Drevets WC, Rofael H, van der Ark P, Kent JM, Kezic I, et al. A randomized Phase 2 study to evaluate the orexin-2 receptor antagonist seltorexant in individuals with insomnia without psychiatric comorbidity. J Psychopharmacol 2018, 32: 668–677.

    PubMed  Google Scholar 

  79. Asai Y, Sano H, Miyazaki M, Iwakura M, Maeda Y, Hara M. Suvorexant (Belsomra((R)) tablets 10, 15, and 20 mg): Japanese drug-use results survey. Drugs R D 2019, 19: 27–46.

    CAS  PubMed  Google Scholar 

  80. Rhyne DN, Anderson SL. Suvorexant in insomnia: efficacy, safety and place in therapy. Ther Adv Drug Saf 2015, 6: 189–195.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Schroeck JL, Ford J, Conway EL, Kurtzhalts KE, Gee ME, Vollmer KA, et al. Review of safety and efficacy of sleep medicines in older adults. Clin Ther 2016, 38: 2340–2372.

    CAS  PubMed  Google Scholar 

  82. Hatano M, Kamei H, Inagaki R, Matsuzaki H, Hanya M, Yamada S, et al. Assessment of switching to suvorexant versus the use of add-on suvorexant in combination with benzodiazepine receptor agonists in insomnia patients: a retrospective study. Clin Psychopharmacol Neurosci 2018, 16: 184–189.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Sutton EL. Profile of suvorexant in the management of insomnia. Drug Des Devel Ther 2015, 9: 6035–6042.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Petrous J, Furmaga K. Adverse reaction with suvorexant for insomnia: acute worsening of depression with emergence of suicidal thoughts. BMJ Case Rep 2017, 2017: bcr-2017-222037.

  85. Tung LW, Lu GL, Lee YH, Yu L, Lee HJ, Leishman E, et al. Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons. Nat Commun 2016, 7: 12199.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Cengiz M, Karaj V, Kocabasoglu N, Gozubatik-Celik G, Dirican A, Bayoglu B. Orexin/hypocretin receptor, Orx1, gene variants are associated with major depressive disorder. Int J Psychiatry Clin Pract 2019, 23: 114–121.

    CAS  PubMed  Google Scholar 

  87. Fitch TE, Benvenga MJ, Jesudason CD, Zink C, Vandergriff AB, Menezes MM, et al. LSN2424100: a novel, potent orexin-2 receptor antagonist with selectivity over orexin-1 receptors and activity in an animal model predictive of antidepressant-like efficacy. Front Neurosci 2014, 8: 5.

    PubMed  PubMed Central  Google Scholar 

  88. Nollet M, Gaillard P, Tanti A, Girault V, Belzung C, Leman S. Neurogenesis-independent antidepressant-like effects on behavior and stress axis response of a dual orexin receptor antagonist in a rodent model of depression. Neuropsychopharmacology 2012, 37: 2210–2221.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Nakamura M, Nagamine T. Neuroendocrine, autonomic, and metabolic responses to an orexin antagonist, suvorexant, in psychiatric patients with insomnia. Innov Clin Neurosci 2017, 14: 30–37.

    PubMed  PubMed Central  Google Scholar 

  90. Connor KM, Ceesay P, Hutzelmann J, Snavely D, Krystal AD, Trivedi MH, et al. Phase II proof-of-concept trial of the orexin receptor antagonist filorexant (MK-6096) in patients with major depressive disorder. Int J Neuropsychopharmacol 2017, 20: 613–618.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Dustrude ET, Caliman IF, Bernabe CS, Fitz SD, Grafe LA, Bhatnagar S, et al. Orexin depolarizes central amygdala neurons via orexin receptor 1, phospholipase c and sodium-calcium exchanger and modulates conditioned fear. Front Neurosci 2018, 12: 934.

    PubMed  PubMed Central  Google Scholar 

  92. Park SC, Kim YK. A novel bio-psychosocial-behavioral treatment model of panic disorder. Psychiatry Investig 2019, 16: 4–15.

    PubMed  Google Scholar 

  93. Abreu AR, Molosh AI, Johnson PL, Shekhar A. Role of medial hypothalamic orexin system in panic, phobia and hypertension. Brain Res 2018. https://doi.org/10.1016/j.brainres.2018.09.010.

  94. Johnson PL, Truitt W, Fitz SD, Minick PE, Dietrich A, Sanghani S, et al. A key role for orexin in panic anxiety. Nat Med 2010, 16: 111–115.

    CAS  PubMed  Google Scholar 

  95. Gottschalk MG, Richter J, Ziegler C, Schiele MA, Mann J, Geiger MJ, et al. Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes. Transl Psychiatry 2019, 9: 75.

    PubMed  PubMed Central  Google Scholar 

  96. Johnson PL, Samuels BC, Fitz SD, Lightman SL, Lowry CA, Shekhar A. Activation of the orexin 1 receptor is a critical component of CO2-mediated anxiety and hypertension but not bradycardia. Neuropsychopharmacology 2012, 37: 1911–1922.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Kordi Jaz E, Moghimi A, Fereidoni M, Asadi S, Shamsizadeh A, Roohbakhsh A. SB-334867, an orexin receptor 1 antagonist, decreased seizure and anxiety in pentylenetetrazol-kindled rats. Fundam Clin Pharmacol 2017, 31: 201–207.

    CAS  PubMed  Google Scholar 

  98. Blume SR, Nam H, Luz S, Bangasser DA, Bhatnagar S. Sex- and age-dependent effects of orexin 1 receptor blockade on open-field behavior and neuronal activity. Neuroscience 2018, 381: 11–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Bahaaddini M, Khatamsaz S, Esmaeili-Mahani S, Abbasnejad M, Raoof M. The role of trigeminal nucleus caudalis orexin 1 receptor in orofacial pain-induced anxiety in rat. Neuroreport 2016, 27: 1107–1113.

    CAS  PubMed  Google Scholar 

  100. Johnson PL, Samuels BC, Fitz SD, Federici LM, Hammes N, Early MC, et al. Orexin 1 receptors are a novel target to modulate panic responses and the panic brain network. Physiol Behav 2012, 107: 733–742.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Johnson PL, Federici LM, Fitz SD, Renger JJ, Shireman B, Winrow CJ, et al. Orexin 1 and 2 receptor involvement in CO2 -induced panic–associated behavior and autonomic responses. Depress Anxiety 2015, 32: 671–683.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Bonaventure P, Yun S, Johnson PL, Shekhar A, Fitz SD, Shireman BT, et al. A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects. J Pharmacol Exp Ther 2015, 352: 590–601.

    PubMed  PubMed Central  Google Scholar 

  103. Arendt DH, Hassell J, Li H, Achua JK, Guarnieri DJ, Dileone RJ, et al. Anxiolytic function of the orexin 2/hypocretin A receptor in the basolateral amygdala. Psychoneuroendocrinology 2014, 40: 17–26.

    CAS  PubMed  Google Scholar 

  104. Muschamp JW, Hollander JA, Thompson JL, Voren G, Hassinger LC, Onvani S, et al. Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area. Proc Natl Acad Sci U S A 2014, 111: E1648–E1655.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Navarro G, Quiroz C, Moreno-Delgado D, Sierakowiak A, McDowell K, Moreno E, et al. Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine. J Neurosci 2015, 35: 6639–6653.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. James MH, Stopper CM, Zimmer BA, Koll NE, Bowrey HE, Aston-Jones G. Increased number and activity of a lateral subpopulation of hypothalamic orexin/hypocretin neurons underlies the expression of an addicted state in rats. Biol Psychiatry 2019, 85: 925–935.

    CAS  PubMed  Google Scholar 

  107. Foltin RW, Evans SM. Hypocretin/orexin antagonists decrease cocaine self-administration by female rhesus monkeys. Drug Alcohol Depend 2018, 188: 318–327.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Hutcheson DM, Quarta D, Halbout B, Rigal A, Valerio E, Heidbreder C. Orexin-1 receptor antagonist SB-334867 reduces the acquisition and expression of cocaine-conditioned reinforcement and the expression of amphetamine-conditioned reward. Behav Pharmacol 2011, 22: 173–181.

    CAS  PubMed  Google Scholar 

  109. Bentzley BS, Aston-Jones G. Orexin-1 receptor signaling increases motivation for cocaine–associated cues. Eur J Neurosci 2015, 41: 1149–1156.

    PubMed  PubMed Central  Google Scholar 

  110. Prince CD, Rau AR, Yorgason JT, Espana RA. Hypocretin/orexin regulation of dopamine signaling and cocaine self-administration is mediated predominantly by hypocretin receptor 1. ACS Chem Neurosci 2015, 6: 138–146.

    CAS  PubMed  Google Scholar 

  111. Schmeichel BE, Herman MA, Roberto M, Koob GF. Hypocretin neurotransmission within the central amygdala mediates escalated cocaine self-administration and stress-induced reinstatement in rats. Biol Psychiatry 2017, 81: 606–615.

    CAS  PubMed  Google Scholar 

  112. Levy KA, Brodnik ZD, Shaw JK, Perrey DA, Zhang Y, Espana RA. Hypocretin receptor 1 blockade produces bimodal modulation of cocaine-associated mesolimbic dopamine signaling. Psychopharmacology (Berl) 2017, 234: 2761–2776.

    CAS  Google Scholar 

  113. Gentile TA, Simmons SJ, Watson MN, Connelly KL, Brailoiu E, Zhang Y, et al. Effects of suvorexant, a dual orexin/hypocretin receptor antagonist, on impulsive behavior associated with cocaine. Neuropsychopharmacology 2018, 43: 1001–1009.

    CAS  PubMed  Google Scholar 

  114. Gentile TA, Simmons SJ, Barker DJ, Shaw JK, Espana RA, Muschamp JW. Suvorexant, an orexin/hypocretin receptor antagonist, attenuates motivational and hedonic properties of cocaine. Addict Biol 2018, 23: 247–255.

    CAS  PubMed  Google Scholar 

  115. Schoedel KA, Sun H, Sellers EM, Faulknor J, Levy-Cooperman N, Li X, et al. Assessment of the abuse potential of the orexin receptor antagonist, suvorexant, compared with zolpidem in a randomized crossover study. J Clin Psychopharmacol 2016, 36: 314–323.

    CAS  PubMed  Google Scholar 

  116. Born S, Gauvin DV, Mukherjee S, Briscoe R. Preclinical assessment of the abuse potential of the orexin receptor antagonist, suvorexant. Regul Toxicol Pharmacol 2017, 86: 181–192.

    CAS  PubMed  Google Scholar 

  117. Anderson RI, Moorman DE, Becker HC. Contribution of dynorphin and orexin neuropeptide systems to the motivational effects of alcohol. Handb Exp Pharmacol 2018, 248: 473–503.

    PubMed  PubMed Central  Google Scholar 

  118. Mayannavar S, Rashmi KS, Rao YD, Yadav S, Ganaraja B. Effect of Orexin A antagonist (SB-334867) infusion into the nucleus accumbens on consummatory behavior and alcohol preference in Wistar rats. Indian J Pharmacol 2016, 48: 53–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Lopez MF, Moorman DE, Aston-Jones G, Becker HC. The highly selective orexin/hypocretin 1 receptor antagonist GSK1059865 potently reduces ethanol drinking in ethanol dependent mice. Brain Res 2016, 1636: 74–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Dhaher R, Hauser SR, Getachew B, Bell RL, McBride WJ, McKinzie DL, et al. The Orexin-1 receptor antagonist SB-334867 reduces alcohol relapse drinking, but not alcohol-seeking, in alcohol-preferring (P) rats. J Addict Med 2010, 4: 153–159.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Moorman DE, James MH, Kilroy EA, Aston-Jones G. Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats. Brain Res 2017, 1654: 34–42.

    CAS  PubMed  Google Scholar 

  122. Quarta D, Valerio E, Hutcheson DM, Hedou G, Heidbreder C. The orexin-1 receptor antagonist SB-334867 reduces amphetamine-evoked dopamine outflow in the shell of the nucleus accumbens and decreases the expression of amphetamine sensitization. Neurochem Int 2010, 56: 11–15.

    CAS  PubMed  Google Scholar 

  123. Lupina M, Tarnowski M, Baranowska-Bosiacka I, Talarek S, Listos P, Kotlinska J, et al. SB-334867 (an Orexin-1 Receptor Antagonist) effects on morphine-induced sensitization in mice-a view on receptor mechanisms. Mol Neurobiol 2018, 55: 8473–8485.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Sharf R, Guarnieri DJ, Taylor JR, DiLeone RJ. Orexin mediates morphine place preference, but not morphine-induced hyperactivity or sensitization. Brain Res 2010, 1317: 24–32.

    CAS  PubMed  Google Scholar 

  125. Porter-Stransky KA, Bentzley BS, Aston-Jones G. Individual differences in orexin-I receptor modulation of motivation for the opioid remifentanil. Addict Biol 2017, 22: 303–317.

    CAS  PubMed  Google Scholar 

  126. Sharf R, Sarhan M, Dileone RJ. Orexin mediates the expression of precipitated morphine withdrawal and concurrent activation of the nucleus accumbens shell. Biol Psychiatry 2008, 64: 175–183.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Davoudi M, Azizi H, Mirnajafi-Zadeh J, Semnanian S. The blockade of GABAA receptors attenuates the inhibitory effect of orexin type 1 receptors antagonist on morphine withdrawal syndrome in rats. Neurosci Lett 2016, 617: 201–206.

    CAS  PubMed  Google Scholar 

  128. Hooshmand B, Azizi H, Javan M, Semnanian S. Intra-LC microinjection of orexin type-1 receptor antagonist SB-334867 attenuates the expression of glutamate-induced opiate withdrawal like signs during the active phase in rats. Neurosci Lett 2017, 636: 276–281.

    CAS  PubMed  Google Scholar 

  129. Farahimanesh S, Zarrabian S, Haghparast A. Role of orexin receptors in the ventral tegmental area on acquisition and expression of morphine-induced conditioned place preference in the rats. Neuropeptides 2017, 66: 45–51.

    CAS  PubMed  Google Scholar 

  130. Ebrahimian F, Naghavi FS, Yazdi F, Sadeghzadeh F, Taslimi Z, Haghparast A. Differential roles of orexin receptors within the dentate gyrus in stress- and drug priming-induced reinstatement of conditioned place preference in rats. Behav Neurosci 2016, 130: 91–102.

    CAS  PubMed  Google Scholar 

  131. Parsania S, Moradi M, Fatahi Z, Haghparast A. Involvement of orexin-1 and orexin-2 receptors within the dentate gyrus of the hippocampus in the acquisition, expression and extinction of lateral hypothalamic-induced conditioned place preference in the rats. Brain Res 2016, 1639: 149–160.

    CAS  PubMed  Google Scholar 

  132. Barson JR, Ho HT, Leibowitz SF. Anterior thalamic paraventricular nucleus is involved in intermittent access ethanol drinking: role of orexin receptor 2. Addict Biol 2015, 20: 469–481.

    CAS  PubMed  Google Scholar 

  133. Schmeichel BE, Barbier E, Misra KK, Contet C, Schlosburg JE, Grigoriadis D, et al. Hypocretin receptor 2 antagonism dose-dependently reduces escalated heroin self-administration in rats. Neuropsychopharmacology 2015, 40: 1123–1129.

    CAS  PubMed  Google Scholar 

  134. Steiner MA, Lecourt H, Jenck F. The dual orexin receptor antagonist almorexant, alone and in combination with morphine, cocaine and amphetamine, on conditioned place preference and locomotor sensitization in the rat. Int J Neuropsychopharmacol 2013, 16: 417–432.

    CAS  PubMed  Google Scholar 

  135. Srinivasan S, Simms JA, Nielsen CK, Lieske SP, Bito-Onon JJ, Yi H, et al. The dual orexin/hypocretin receptor antagonist, almorexant, in the ventral tegmental area attenuates ethanol self-administration. PLoS One 2012, 7: e44726.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Steiner MA, Lecourt H, Strasser DS, Brisbare-Roch C, Jenck F. Differential effects of the dual orexin receptor antagonist almorexant and the GABA(A)-alpha1 receptor modulator zolpidem, alone or combined with ethanol, on motor performance in the rat. Neuropsychopharmacology 2011, 36: 848–856.

    CAS  PubMed  Google Scholar 

  137. Hoch M, Hay JL, Hoever P, de Kam ML, te Beek ET, van Gerven JM, et al. Dual orexin receptor antagonism by almorexant does not potentiate impairing effects of alcohol in humans. Eur Neuropsychopharmacol 2013, 23: 107–117.

    CAS  PubMed  Google Scholar 

  138. Sanchez-Alavez M, Benedict J, Wills DN, Ehlers CL. Effect of suvorexant on event-related oscillations and EEG sleep in rats exposed to chronic intermittent ethanol vapor and protracted withdrawal. Sleep 2019, 42: zsz020.

  139. Campbell EJ, Marchant NJ, Lawrence AJ. A sleeping giant: suvorexant for the treatment of alcohol use disorder? Brain Res 2018; e-pub ahead of print 3 August 2018; https://doi.org/10.1016/j.brainres.2018.08.005.

  140. Plaza-Zabala A, Flores A, Maldonado R, Berrendero F. Hypocretin/orexin signaling in the hypothalamic paraventricular nucleus is essential for the expression of nicotine withdrawal. Biol Psychiatry 2012, 71: 214–223.

    CAS  PubMed  Google Scholar 

  141. Nishizawa D, Kasai S, Hasegawa J, Sato N, Yamada H, Tanioka F, et al. Associations between the orexin (hypocretin) receptor 2 gene polymorphism Val308Ile and nicotine dependence in genome-wide and subsequent association studies. Mol Brain 2015, 8: 50.

    PubMed  PubMed Central  Google Scholar 

  142. Khoo SY, Clemens KJ, McNally GP. Palatable food self-administration and reinstatement are not affected by dual orexin receptor antagonism. Prog Neuropsychopharmacol Biol Psychiatry 2018, 87: 147–157.

    CAS  PubMed  Google Scholar 

  143. Khoo SY, McNally GP, Clemens KJ. The dual orexin receptor antagonist TCS1102 does not affect reinstatement of nicotine-seeking. PLoS One 2017, 12: e0173967.

    PubMed  PubMed Central  Google Scholar 

  144. Sharf R, Sarhan M, Brayton CE, Guarnieri DJ, Taylor JR, DiLeone RJ. Orexin signaling via the orexin 1 receptor mediates operant responding for food reinforcement. Biol Psychiatry 2010, 67: 753–760.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Flores A, Maldonado R, Berrendero F. The hypocretin/orexin receptor-1 as a novel target to modulate cannabinoid reward. Biol Psychiatry 2014, 75: 499–507.

    CAS  PubMed  Google Scholar 

  146. Brodnik ZD, Alonso IP, Xu W, Zhang Y, Kortagere S, Espana RA. Hypocretin receptor 1 involvement in cocaine-associated behavior: Therapeutic potential and novel mechanistic insights. Brain Res 2018. https://doi.org/10.1016/j.brainres.2018.07.027.

    Article  PubMed  Google Scholar 

  147. Perrey DA, Zhang Y. Therapeutics development for addiction: orexin-1 receptor antagonists. Brain Res 2018. https://doi.org/10.1016/j.brainres.2018.08.025.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Dubey AK, Handu SS, Mediratta PK. Suvorexant: The first orexin receptor antagonist to treat insomnia. J Pharmacol Pharmacother 2015, 6: 118–121.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Coleman PJ, Cox CD, Roecker AJ. Discovery of dual orexin receptor antagonists (DORAs) for the treatment of insomnia. Curr Top Med Chem 2011, 11: 696–725.

    CAS  PubMed  Google Scholar 

  150. Nocjar C, Zhang J, Feng P, Panksepp J. The social defeat animal model of depression shows diminished levels of orexin in mesocortical regions of the dopamine system, and of dynorphin and orexin in the hypothalamus. Neuroscience 2012, 218: 138–153.

    CAS  PubMed  Google Scholar 

  151. Winrow CJ, Gotter AL, Cox CD, Tannenbaum PL, Garson SL, Doran SM, et al. Pharmacological characterization of MK-6096 - a dual orexin receptor antagonist for insomnia. Neuropharmacology 2012, 62: 978–987.

    CAS  PubMed  Google Scholar 

  152. Herring WJ, Snyder E, Budd K, Hutzelmann J, Snavely D, Liu K, et al. Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology 2012, 79: 2265–2274.

    CAS  PubMed  Google Scholar 

  153. Nishimura S, Nakao M. Cost-effectiveness analysis of suvorexant for the treatment of Japanese elderly patients with chronic insomnia in a virtual cohort. J Med Econ 2018, 21: 698–703.

    PubMed  Google Scholar 

  154. Svetnik V, Snyder ES, Tao P, Scammell TE, Roth T, Lines C, et al. Insight Into reduction of wakefulness by suvorexant in patients with insomnia: analysis of wake bouts. Sleep 2018. https://doi.org/10.1093/sleep/zsx178.

    Article  PubMed  Google Scholar 

  155. Hoever P, de Haas S, Winkler J, Schoemaker RC, Chiossi E, van Gerven J, et al. Orexin receptor antagonism, a new sleep-promoting paradigm: an ascending single-dose study with almorexant. Clin Pharmacol Ther 2010, 87: 593–600.

    CAS  PubMed  Google Scholar 

  156. Black SW, Morairty SR, Fisher SP, Chen TM, Warrier DR, Kilduff TS. Almorexant promotes sleep and exacerbates cataplexy in a murine model of narcolepsy. Sleep 2013, 36: 325–336.

    PubMed  PubMed Central  Google Scholar 

  157. Morairty SR, Wilk AJ, Lincoln WU, Neylan TC, Kilduff TS. The hypocretin/orexin antagonist almorexant promotes sleep without impairment of performance in rats. Front Neurosci 2014, 8: 3.

    PubMed  PubMed Central  Google Scholar 

  158. Black J, Pillar G, Hedner J, Polo O, Berkani O, Mangialaio S, et al. Efficacy and safety of almorexant in adult chronic insomnia: a randomized placebo-controlled trial with an active reference. Sleep Med 2017, 36: 86–94.

    PubMed  Google Scholar 

  159. Roth T, Black J, Cluydts R, Charef P, Cavallaro M, Kramer F, et al. Dual orexin receptor antagonist, almorexant, in elderly patients with primary insomnia: a randomized, controlled study. Sleep 2017. https://doi.org/10.1093/sleep/zsw034.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Yoshida Y, Naoe Y, Terauchi T, Ozaki F, Doko T, Takemura A, et al. Discovery of (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluor opyridin-2-yl)cyclopropanecarboxamide (E2006): a potent and efficacious oral orexin receptor antagonist. J Med Chem 2015, 58: 4648–4664.

    CAS  PubMed  Google Scholar 

  161. Whitman DB, Cox CD, Breslin MJ, Brashear KM, Schreier JD, Bogusky MJ, et al. Discovery of a potent, CNS-penetrant orexin receptor antagonist based on an n,n-disubstituted-1,4-diazepane scaffold that promotes sleep in rats. ChemMedChem 2009, 4: 1069–1074.

    CAS  PubMed  Google Scholar 

  162. Coleman PJ, Schreier JD, Roecker AJ, Mercer SP, McGaughey GB, Cox CD, et al. Discovery of 3,9-diazabicyclo[4.2.1]nonanes as potent dual orexin receptor antagonists with sleep-promoting activity in the rat. Bioorg Med Chem Lett 2010, 20: 4201–4205.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This review was supported by the National Natural Science Foundation of China (81701312 and 81521063) and the Interdisciplinary Medicine Seed Fund of Peking University (BMU2018MX024).

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  1. Ying Han and Kai Yuan have contributed equally to this work.

Authors and Affiliations

  1. National Institute of Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, 100191, China

    Ying Han & Lin Lu

  2. Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, 100191, China

    Kai Yuan, Yongbo Zheng & Lin Lu

  3. Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China

    Kai Yuan & Lin Lu

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  1. Ying Han
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Han, Y., Yuan, K., Zheng, Y. et al. Orexin Receptor Antagonists as Emerging Treatments for Psychiatric Disorders. Neurosci. Bull. 36, 432–448 (2020). https://doi.org/10.1007/s12264-019-00447-9

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