CNS Drugs

, Volume 33, Issue 10, pp 981–999 | Cite as

Pharmacological Manipulation of the Circadian Clock: A Possible Approach to the Management of Bipolar Disorder

  • Alessandra Porcu
  • Robert Gonzalez
  • Michael J. McCarthyEmail author
Review Article


Bipolar disorder (BD) is a mood disorder with genetic and neurobiological underpinnings, characterized primarily by recurrent episodes of mania and depression, with notable disruptions in rhythmic behaviors such as sleep, energy, appetite and attention. The chronobiological links to BD are further supported by the effectiveness of various treatment modalities such as bright light, circadian phase advance, and mood-stabilizing drugs such as lithium that have effects on the circadian clock. Over the past 30 years, the neurobiology of the circadian clock has been exquisitely described and there now exists a detailed knowledge of key signaling pathways, neurotransmitters and signaling mechanisms that regulate various dimensions of circadian clock function. With this new wealth of information, it is becoming increasingly plausible that new drugs for BD could be made by targeting molecular elements of the circadian clock. However, circadian rhythms are multidimensional and complex, involving unique, time-dependent factors that are not typically considered in drug development. We review the organization of the circadian clock in the central nervous system and briefly summarize data implicating the circadian clock in BD. We then consider some of the unique aspects of the circadian clock as a drug target in BD, discuss key methodological considerations and evaluate some of the candidate clock pathways and systems that could serve as potential targets for novel mood stabilizers. We expect this work will serve as a roadmap to facilitate the development of compounds acting on the circadian clock for the treatment of BD.


Compliance with Ethical Standards

This work was conducted in accordance with all pertinent standards for ethical research.


MJM is supported by a VA Merit Award (U.S. Department of Veterans Affairs; BX003431) and a research award from the Prentiss Foundation. The funders had no role in the preparation of the manuscript or decision to publish.

Conflict of interest

MJM has received consulting fees from Janssen Pharmaceuticals in the past 12 months. AP and RG have no conflicts to report.


  1. 1.
    Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011;68(3):241–51. Scholar
  2. 2.
    McCarthy MJ, Welsh DK. Cellular circadian clocks in mood disorders. J Biol Rhythms. 2012;27(5):339–52. Scholar
  3. 3.
    Landgraf D, McCarthy MJ, Welsh DK. Circadian clock and stress interactions in the molecular biology of psychiatric disorders. Curr Psychiatry Rep. 2014;16(10):483. Scholar
  4. 4.
    Maruani J, Anderson G, Etain B, Lejoyeux M, Bellivier F, Geoffroy PA. The neurobiology of adaptation to seasons: relevance and correlations in bipolar disorders. Chronobiol Int. 2018;35(10):1335–53. Scholar
  5. 5.
    Charney AW, Ruderfer DM, Stahl EA, Moran JL, Chambert K, Belliveau RA, et al. Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder. Transl Psychiatry. 2017;7(1):e993. Scholar
  6. 6.
    Malhi GS, Fritz K, Elangovan P, Irwin L. Mixed States: modelling and management. CNS Drugs. 2019;33(4):301–13. Scholar
  7. 7.
    Gonzalez R, Suppes T, Zeitzer J, McClung C, Tamminga C, Tohen M, et al. The association between mood state and chronobiological characteristics in bipolar I disorder: a naturalistic, variable cluster analysis-based study. Int J Bipolar Disord. 2018;6(1):5. Scholar
  8. 8.
    McCarthy MJ. Missing a beat: assessment of circadian rhythm abnormalities in bipolar disorder in the genomic era. Psychiatr Genet. 2019;29(2):29–36. Scholar
  9. 9.
    Frank E, Kupfer DJ, Thase ME, Mallinger AG, Swartz HA, Fagiolini AM, et al. Two-year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder. Arch Gen Psychiatry. 2005;62(9):996–1004. Scholar
  10. 10.
    Roecklein KA, Wong PM, Miller MA, Donofry SD, Kamarck ML, Brainard GC. Melanopsin, photosensitive ganglion cells, and seasonal affective disorder. Neurosci Biobehav Rev. 2013;37(3):229–39. Scholar
  11. 11.
    Wittmann M, Dinich J, Merrow M, Roenneberg T. Social jetlag: misalignment of biological and social time. Chronobiol Int. 2006;23(1–2):497–509. Scholar
  12. 12.
    Mohawk JA, Green CB, Takahashi JS. Central and peripheral circadian clocks in mammals. Annu Rev Neurosci. 2012;35:445–62. Scholar
  13. 13.
    Welsh DK, Takahashi JS, Kay SA. Suprachiasmatic nucleus: cell autonomy and network properties. Annu Rev Physiol. 2010;72:551–77. Scholar
  14. 14.
    Schmidt TM, Chen SK, Hattar S. Intrinsically photosensitive retinal ganglion cells: many subtypes, diverse functions. Trends Neurosci. 2011;34(11):572–80. Scholar
  15. 15.
    Vitaterna MH, King DP, Chang AM, Kornhauser JM, Lowrey PL, McDonald JD, et al. Mutagenesis and mapping of a mouse gene, clock, essential for circadian behavior. Science. 1994;264(5159):719–25.CrossRefGoogle Scholar
  16. 16.
    Landgraf D, Long JE, Proulx CD, Barandas R, Malinow R, Welsh DK. Genetic disruption of circadian rhythms in the suprachiasmatic nucleus causes helplessness, behavioral despair, and anxiety-like behavior in mice. Biol Psychiatry. 2016;80(11):827–35. Scholar
  17. 17.
    Paul JR, Davis JA, Goode LK, Becker BK, Fusilier A, Meador-Woodruff A, et al. Circadian regulation of membrane physiology in neural oscillators throughout the brain. Eur J Neurosci. 2019. Scholar
  18. 18.
    LeGates TA, Fernandez DC, Hattar S. Light as a central modulator of circadian rhythms, sleep and affect. Nat Rev Neurosci. 2014;15(7):443–54. Scholar
  19. 19.
    Fernandez DC, Fogerson PM, Lazzerini Ospri L, Thomsen MB, Layne RM, Severin D, et al. Light affects mood and learning through distinct retina–brain pathways. Cell. 2018;175(1):71–84. (e18).CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    LeGates TA, Altimus CM, Wang H, Lee HK, Yang S, Zhao H, et al. Aberrant light directly impairs mood and learning through melanopsin-expressing neurons. Nature. 2012;491(7425):594–8. Scholar
  21. 21.
    Sidor MM, Spencer SM, Dzirasa K, Parekh PK, Tye KM, Warden MR, et al. Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice. Mol Psychiatry. 2015;20(11):1406–19. Scholar
  22. 22.
    Ferris MJ, Espana RA, Locke JL, Konstantopoulos JK, Rose JH, Chen R, et al. Dopamine transporters govern diurnal variation in extracellular dopamine tone. Proc Natl Acad Sci USA. 2014;111(26):E2751–9. Scholar
  23. 23.
    Ozburn AR, Falcon E, Twaddle A, Nugent AL, Gillman AG, Spencer SM, et al. Direct regulation of diurnal Drd3 expression and cocaine reward by NPAS2. Biol Psychiatry. 2015;77(5):425–33. Scholar
  24. 24.
    Mukherjee S, Coque L, Cao JL, Kumar J, Chakravarty S, Asaithamby A, et al. Knockdown of clock in the ventral tegmental area through RNA interference results in a mixed state of mania and depression-like behavior. Biol Psychiatry. 2010;68(6):503–11. Scholar
  25. 25.
    Roybal K, Theobold D, Graham A, DiNieri JA, Russo SJ, Krishnan V, et al. Mania-like behavior induced by disruption of clock. Proc Natl Acad Sci USA. 2007;104(15):6406–11. Scholar
  26. 26.
    Mure LS, Le HD, Benegiamo G, Chang MW, Rios L, Jillani N, et al. Diurnal transcriptome atlas of a primate across major neural and peripheral tissues. Science. 2018. Scholar
  27. 27.
    Landgraf D, Long JE, Welsh DK. Depression-like behaviour in mice is associated with disrupted circadian rhythms in nucleus accumbens and periaqueductal grey. Eur J Neurosci. 2016;43(10):1309–20. Scholar
  28. 28.
    Freyberg Z, McCarthy MJ. Dopamine D2 receptors and the circadian clock reciprocally mediate antipsychotic drug-induced metabolic disturbances. NPJ Schizophr. 2017;3:17. Scholar
  29. 29.
    Barandas R, Landgraf D, McCarthy MJ, Welsh DK. Circadian clocks as modulators of metabolic comorbidity in psychiatric disorders. Curr Psychiatry Rep. 2015;17(12):98. Scholar
  30. 30.
    Partch CL, Green CB, Takahashi JS. Molecular architecture of the mammalian circadian clock. Trends Cell Biol. 2014;24(2):90–9. Scholar
  31. 31.
    Harada Y, Sakai M, Kurabayashi N, Hirota T, Fukada Y. Ser-557-phosphorylated mCRY2 is degraded upon synergistic phosphorylation by glycogen synthase kinase-3 beta. J Biol Chem. 2005;280(36):31714–21. Scholar
  32. 32.
    Yin L, Wang J, Klein PS, Lazar MA. Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock. Science. 2006;311(5763):1002–5. Scholar
  33. 33.
    Sahar S, Zocchi L, Kinoshita C, Borrelli E, Sassone-Corsi P. Regulation of BMAL1 protein stability and circadian function by GSK3beta-mediated phosphorylation. PLoS One. 2010;5(1):e8561. Scholar
  34. 34.
    Iitaka C, Miyazaki K, Akaike T, Ishida N. A role for glycogen synthase kinase-3beta in the mammalian circadian clock. J Biol Chem. 2005;280(33):29397–402. Scholar
  35. 35.
    Luciano AK, Zhou W, Santana JM, Kyriakides C, Velazquez H, Sessa WC. Clock phosphorylation by AKT regulates its nuclear accumulation and circadian gene expression in peripheral tissues. J Biol Chem. 2018;293(23):9126–36. Scholar
  36. 36.
    Sanada K, Harada Y, Sakai M, Todo T, Fukada Y. Serine phosphorylation of mCRY1 and mCRY2 by mitogen-activated protein kinase. Genes Cells. 2004;9(8):697–708. Scholar
  37. 37.
    Klein PS, Melton DA. A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA. 1996;93(16):8455–9.CrossRefGoogle Scholar
  38. 38.
    Berridge MJ, Downes CP, Hanley MR. Neural and developmental actions of lithium: a unifying hypothesis. Cell. 1989;59(3):411–9.CrossRefGoogle Scholar
  39. 39.
    McCarthy M, Wei H, Nievergelt C, Stautland A, Maihofer A, Welsh DK. Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder. Neuropsychopharmacology. 2019;44:620–8.CrossRefGoogle Scholar
  40. 40.
    Hirota T, Lewis WG, Liu AC, Lee JW, Schultz PG, Kay SA. A chemical biology approach reveals period shortening of the mammalian circadian clock by specific inhibition of GSK-3beta. Proc Natl Acad Sci USA. 2008;105(52):20746–51. Scholar
  41. 41.
    McEachron DL, Kripke DF, Wyborney VG. Lithium promotes entrainment of rats to long circadian light-dark cycles. Psychiatry Res. 1981;5(1):1–9.CrossRefGoogle Scholar
  42. 42.
    Kripke DF, Wyborney VG. Lithium slows rat circadian activity rhythms. Life Sci. 1980;26(16):1319–21.CrossRefGoogle Scholar
  43. 43.
    Kripke DF, Judd LL, Hubbard B, Janowsky DS, Huey LY. The effect of lithium carbonate on the circadian rhythm of sleep in normal human subjects. Biol Psychiatry. 1979;14(3):545–8.PubMedGoogle Scholar
  44. 44.
    Welsh DK, Moore-Ede MC. Lithium lengthens circadian period in a diurnal primate, Saimiri sciureus. Biol Psychiatry. 1990;28(2):117–26.CrossRefGoogle Scholar
  45. 45.
    McCarthy MJ, Wei H, Marnoy Z, Darvish RM, McPhie DL, Cohen BM, et al. Genetic and clinical factors predict lithium’s effects on PER2 gene expression rhythms in cells from bipolar disorder patients. Transl Psychiatry. 2013;3:e318. Scholar
  46. 46.
    Abe M, Herzog ED, Block GD. Lithium lengthens the circadian period of individual suprachiasmatic nucleus neurons. Neuroreport. 2000;11(14):3261–4.CrossRefGoogle Scholar
  47. 47.
    McCarthy MJ, Wei H, Landgraf D, Le Roux MJ, Welsh DK. Disinhibition of the extracellular-signal-regulated kinase restores the amplification of circadian rhythms by lithium in cells from bipolar disorder patients. Eur Neuropsychopharmacol. 2016;26(8):1310–9. Scholar
  48. 48.
    McCarthy MJ, LeRoux M, Wei H, Beesley S, Kelsoe JR, Welsh DK. Calcium channel genes associated with bipolar disorder modulate lithium’s amplification of circadian rhythms. Neuropharmacology. 2015. Scholar
  49. 49.
    Schnell A, Sandrelli F, Ranc V, Ripperger JA, Brai E, Alberi L, et al. Mice lacking circadian clock components display different mood-related behaviors and do not respond uniformly to chronic lithium treatment. Chronobiol Int. 2015;32(8):1075–89. Scholar
  50. 50.
    Harvey AG. Sleep and circadian rhythms in bipolar disorder: seeking synchrony, harmony, and regulation. Am J Psychiatry. 2008;165(7):820–9. Scholar
  51. 51.
    Harvey AG, Schmidt DA, Scarna A, Semler CN, Goodwin GM. Sleep-related functioning in euthymic patients with bipolar disorder, patients with insomnia, and subjects without sleep problems. Am J Psychiatry. 2005;162(1):50–7. Scholar
  52. 52.
    Duffy A, Alda M, Hajek T, Sherry SB, Grof P. Early stages in the development of bipolar disorder. J Affect Disord. 2010;121(1–2):127–35. Scholar
  53. 53.
    Jackson A, Cavanagh J, Scott J. A systematic review of manic and depressive prodromes. J Affect Disord. 2003;74(3):209–17.CrossRefGoogle Scholar
  54. 54.
    Skjelstad DV, Malt UF, Holte A. Symptoms and signs of the initial prodrome of bipolar disorder: a systematic review. J Affect Disord. 2010;126(1–2):1–13. Scholar
  55. 55.
    Rucklidge JJ. Retrospective parent report of psychiatric histories: do checklists reveal specific prodromal indicators for postpubertal-onset pediatric bipolar disorder? Bipolar Disord. 2008;10(1):56–66. Scholar
  56. 56.
    Eidelman P, Talbot LS, Gruber J, Harvey AG. Sleep, illness course, and concurrent symptoms in inter-episode bipolar disorder. J Behav Ther Exp Psychiatry. 2010;41(2):145–9. Scholar
  57. 57.
    Colombo C, Benedetti F, Barbini B, Campori E, Smeraldi E. Rate of switch from depression into mania after therapeutic sleep deprivation in bipolar depression. Psychiatry Res. 1999;86(3):267–70.CrossRefGoogle Scholar
  58. 58.
    Eidelman P, Talbot LS, Gruber J, Hairston I, Harvey AG. Sleep architecture as correlate and predictor of symptoms and impairment in inter-episode bipolar disorder: taking on the challenge of medication effects. J Sleep Res. 2010;19(4):516–24. Scholar
  59. 59.
    Hudson JI, Lipinski JF, Keck PE Jr, Aizley HG, Lukas SE, Rothschild AJ, et al. Polysomnographic characteristics of young manic patients Comparison with unipolar depressed patients and normal control subjects. Arch Gen Psychiatry. 1992;49(5):378–83.CrossRefGoogle Scholar
  60. 60.
    Gruber J, Harvey AG, Wang PW, Brooks JO 3rd, Thase ME, Sachs GS, et al. Sleep functioning in relation to mood, function, and quality of life at entry to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). J Affect Disord. 2009;114(1–3):41–9. Scholar
  61. 61.
    Jones SH, Hare DJ, Evershed K. Actigraphic assessment of circadian activity and sleep patterns in bipolar disorder. Bipolar Disord. 2005;7(2):176–86. Scholar
  62. 62.
    Gonzalez R, Tamminga CA, Tohen M, Suppes T. The relationship between affective state and the rhythmicity of activity in bipolar disorder. J Clin Psychiatry. 2014;75(4):e317–22. Scholar
  63. 63.
    McKenna BS, Drummond SP, Eyler LT. Associations between circadian activity rhythms and functional brain abnormalities among euthymic bipolar patients: a preliminary study. J Affect Disord. 2014;164:101–6. Scholar
  64. 64.
    Pagani L, St Clair PA, Teshiba TM, Service SK, Fears SC, Araya C, et al. Genetic contributions to circadian activity rhythm and sleep pattern phenotypes in pedigrees segregating for severe bipolar disorder. Proc Natl Acad Sci USA. 2016;113(6):E754–61. Scholar
  65. 65.
    Lyall LM, Wyse CA, Graham N, Ferguson A, Lyall DM, Cullen B, et al. Association of disrupted circadian rhythmicity with mood disorders, subjective wellbeing, and cognitive function: a cross-sectional study of 91 105 participants from the UK Biobank. Lancet Psychiatry. 2018;5(6):507–14. Scholar
  66. 66.
    Teicher MH. Actigraphy and motion analysis: new tools for psychiatry. Harv Rev Psychiatry. 1995;3(1):18–35.CrossRefGoogle Scholar
  67. 67.
    Hu Y, Shmygelska A, Tran D, Eriksson N, Tung JY, Hinds DA. GWAS of 89,283 individuals identifies genetic variants associated with self-reporting of being a morning person. Nat Commun. 2016;7:10448. Scholar
  68. 68.
    Jones SE, Tyrrell J, Wood AR, Beaumont RN, Ruth KS, Tuke MA, et al. Genome-wide association analyses in 128,266 individuals identifies new morningness and sleep duration loci. PLoS Genet. 2016;12(8):e1006125. Scholar
  69. 69.
    Wood J, Birmaher B, Axelson D, Ehmann M, Kalas C, Monk K, et al. Replicable differences in preferred circadian phase between bipolar disorder patients and control individuals. Psychiatry Res. 2009;166(2–3):201–9. Scholar
  70. 70.
    Ahn YM, Chang J, Joo YH, Kim SC, Lee KY, Kim YS. Chronotype distribution in bipolar I disorder and schizophrenia in a Korean sample. Bipolar Disord. 2008;10(2):271–5. Scholar
  71. 71.
    Mansour HA, Wood J, Chowdari KV, Dayal M, Thase ME, Kupfer DJ, et al. Circadian phase variation in bipolar I disorder. Chronobiol Int. 2005;22(3):571–84. Scholar
  72. 72.
    Ehlers CL, Frank E, Kupfer DJ. Social zeitgebers and biological rhythms. A unified approach to understanding the etiology of depression. Arch Gen Psychiatry. 1988;45(10):948–52.CrossRefGoogle Scholar
  73. 73.
    Ashman SB, Monk TH, Kupfer DJ, Clark CH, Myers FS, Frank E, et al. Relationship between social rhythms and mood in patients with rapid cycling bipolar disorder. Psychiatry Res. 1999;86(1):1–8.CrossRefGoogle Scholar
  74. 74.
    Malkoff-Schwartz S, Frank E, Anderson B, Sherrill JT, Siegel L, Patterson D, et al. Stressful life events and social rhythm disruption in the onset of manic and depressive bipolar episodes: a preliminary investigation. Arch Gen Psychiatry. 1998;55(8):702–7.CrossRefGoogle Scholar
  75. 75.
    Wood S, Loudon A. Clocks for all seasons: unwinding the roles and mechanisms of circadian and interval timers in the hypothalamus and pituitary. J Endocrinol. 2014;222(2):R39–59. Scholar
  76. 76.
    Kripke DF, Elliott JA, Welsh DK, Youngstedt SD. Photoperiodic and circadian bifurcation theories of depression and mania. F1000Res. 2015;4:107. Scholar
  77. 77.
    Hakkarainen R, Johansson C, Kieseppa T, Partonen T, Koskenvuo M, Kaprio J, et al. Seasonal changes, sleep length and circadian preference among twins with bipolar disorder. BMC Psychiatry. 2003;3:6. Scholar
  78. 78.
    Cassidy F, Carroll BJ. Seasonal variation of mixed and pure episodes of bipolar disorder. J Affect Disord. 2002;68(1):25–31.CrossRefGoogle Scholar
  79. 79.
    Silverstone T, Romans S, Hunt N, McPherson H. Is there a seasonal pattern of relapse in bipolar affective disorders? A dual northern and southern hemisphere cohort study. Br J Psychiatry. 1995;167(1):58–60. Scholar
  80. 80.
    Shin K, Schaffer A, Levitt AJ, Boyle MH. Seasonality in a community sample of bipolar, unipolar and control subjects. J Affect Disord. 2005;86(1):19–25. Scholar
  81. 81.
    Inder ML, Crowe MT, Porter R. Effect of transmeridian travel and jetlag on mood disorders: evidence and implications. Aust N Z J Psychiatry. 2016;50(3):220–7. Scholar
  82. 82.
    Macchi MM, Bruce JN. Human pineal physiology and functional significance of melatonin. Front Neuroendocrinol. 2004;25(3–4):177–95. Scholar
  83. 83.
    Pacchierotti C, Iapichino S, Bossini L, Pieraccini F, Castrogiovanni P. Melatonin in psychiatric disorders: a review on the melatonin involvement in psychiatry. Front Neuroendocrinol. 2001;22(1):18–32. Scholar
  84. 84.
    Nurnberger JI Jr, Adkins S, Lahiri DK, Mayeda A, Hu K, Lewy A, et al. Melatonin suppression by light in euthymic bipolar and unipolar patients. Arch Gen Psychiatry. 2000;57(6):572–9.CrossRefGoogle Scholar
  85. 85.
    Robillard R, Naismith SL, Rogers NL, Scott EM, Ip TK, Hermens DF, et al. Sleep-wake cycle and melatonin rhythms in adolescents and young adults with mood disorders: comparison of unipolar and bipolar phenotypes. Eur Psychiatry. 2013;28(7):412–6. Scholar
  86. 86.
    Lam RW, Berkowitz AL, Berga SL, Clark CM, Kripke DF, Gillin JC. Melatonin suppression in bipolar and unipolar mood disorders. Psychiatry Res. 1990;33(2):129–34.CrossRefGoogle Scholar
  87. 87.
    Kennedy SH, Kutcher SP, Ralevski E, Brown GM. Nocturnal melatonin and 24-hour 6-sulphatoxymelatonin levels in various phases of bipolar affective disorder. Psychiatry Res. 1996;63(2–3):219–22.CrossRefGoogle Scholar
  88. 88.
    Bullock B, McGlashan EM, Burns AC, Lu BS, Cain SW. Traits related to bipolar disorder are associated with an increased post-illumination pupil response. Psychiatry Res. 2019;278:35–41. Scholar
  89. 89.
    Roecklein K, Wong P, Ernecoff N, Miller M, Donofry S, Kamarck M, et al. The post illumination pupil response is reduced in seasonal affective disorder. Psychiatry Res. 2013;210(1):150–8. Scholar
  90. 90.
    Gaspar L, van de Werken M, Johansson AS, Moriggi E, Owe-Larsson B, Kocks JW, et al. Human cellular differences in cAMP–CREB signaling correlate with light-dependent melatonin suppression and bipolar disorder. Eur J Neurosci. 2014;40(1):2206–15. Scholar
  91. 91.
    Daban C, Vieta E, Mackin P, Young AH. Hypothalamic-pituitary-adrenal axis and bipolar disorder. Psychiatr Clin N Am. 2005;28(2):469–80. Scholar
  92. 92.
    Belvederi Murri M, Prestia D, Mondelli V, Pariante C, Patti S, Olivieri B, et al. The HPA axis in bipolar disorder: systematic review and meta-analysis. Psychoneuroendocrinology. 2016;63:327–42. Scholar
  93. 93.
    Linkowski P, Kerkhofs M, Van Onderbergen A, Hubain P, Copinschi G, L’Hermite-Baleriaux M, et al. The 24-hour profiles of cortisol, prolactin, and growth hormone secretion in mania. Arch Gen Psychiatry. 1994;51(8):616–24.CrossRefGoogle Scholar
  94. 94.
    Linkowski P, Mendlewicz J, Leclercq R, Brasseur M, Hubain P, Golstein J, et al. The 24-hour profile of adrenocorticotropin and cortisol in major depressive illness. J Clin Endocrinol Metab. 1985;61(3):429–38. Scholar
  95. 95.
    Prossin AR, Chandler M, Ryan KA, Saunders EF, Kamali M, Papadopoulos V, et al. Functional TSPO polymorphism predicts variance in the diurnal cortisol rhythm in bipolar disorder. Psychoneuroendocrinology. 2018;89:194–202. Scholar
  96. 96.
    Hirota T, Lee JW, Lewis WG, Zhang EE, Breton G, Liu X, et al. High-throughput chemical screen identifies a novel potent modulator of cellular circadian rhythms and reveals CKIalpha as a clock regulatory kinase. PLoS Biol. 2010;8(12):e1000559. Scholar
  97. 97.
    Takaesu Y, Inoue Y, Ono K, Murakoshi A, Futenma K, Komada Y, et al. Circadian rhythm sleep-wake disorders predict shorter time to relapse of mood episodes in euthymic patients with bipolar disorder: a prospective 48-week study. J Clin Psychiatry. 2018. Scholar
  98. 98.
    Possidente B, Lumia AR, McEldowney S, Rapp M. Fluoxetine shortens circadian period for wheel running activity in mice. Brain Res Bull. 1992;28(4):629–31.CrossRefGoogle Scholar
  99. 99.
    Obrietan K, Impey S, Storm DR. Light and circadian rhythmicity regulate MAP kinase activation in the suprachiasmatic nuclei. Nat Neurosci. 1998;1(8):693–700. Scholar
  100. 100.
    Dziema H, Oatis B, Butcher GQ, Yates R, Hoyt KR, Obrietan K. The ERK/MAP kinase pathway couples light to immediate-early gene expression in the suprachiasmatic nucleus. Eur J Neurosci. 2003;17(8):1617–27.CrossRefGoogle Scholar
  101. 101.
    Gamble KL, Ciarleglio CM. Ryanodine receptors are regulated by the circadian clock and implicated in gating photic entrainment. J Neurosci. 2009;29(38):11717–9. Scholar
  102. 102.
    Schmutz I, Chavan R, Ripperger JA, Maywood ES, Langwieser N, Jurik A, et al. A specific role for the REV-ERBalpha-controlled L-type voltage-gated calcium channel CaV1.2 in resetting the circadian clock in the late night. J Biol Rhythms. 2014;29(4):288–98. Scholar
  103. 103.
    Oster H, Werner C, Magnone MC, Mayser H, Feil R, Seeliger MW, et al. cGMP-dependent protein kinase II modulates mPer1 and mPer2 gene induction and influences phase shifts of the circadian clock. Curr Biol. 2003;13(9):725–33.CrossRefGoogle Scholar
  104. 104.
    Byku M, Gannon RL. Effects of the 5HT1A agonist/antagonist BMY 7378 on light-induced phase advances in hamster circadian activity rhythms during aging. J Biol Rhythms. 2000;15(4):300–5. Scholar
  105. 105.
    Krystal AD, Zammit G. The sleep effects of lurasidone: a placebo-controlled cross-over study using a 4-h phase-advance model of transient insomnia. Hum Psychopharmacol. 2016;31(3):206–16. Scholar
  106. 106.
    Slominski RM, Reiter RJ, Schlabritz-Loutsevitch N, Ostrom RS, Slominski AT. Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol Cell Endocrinol. 2012;351(2):152–66. Scholar
  107. 107.
    Missbach M, Jagher B, Sigg I, Nayeri S, Carlberg C, Wiesenberg I. Thiazolidine diones, specific ligands of the nuclear receptor retinoid Z receptor/retinoid acid receptor-related orphan receptor alpha with potent antiarthritic activity. J Biol Chem. 1996;271(23):13515–22. Scholar
  108. 108.
    Comai S, Gobbi G. Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology. J Psychiatry Neurosci. 2014;39(1):6–21. Scholar
  109. 109.
    Comai S, Lopez-Canul M, De Gregorio D, Posner A, Ettaoussi M, Guarnieri FC, et al. Melatonin MT1 receptor as a novel target in neuropsychopharmacology: MT1 ligands, pathophysiological and therapeutic implications, and perspectives. Pharmacol Res. 2019;144:343–56. Scholar
  110. 110.
    Comai S, Ochoa-Sanchez R, Dominguez-Lopez S, Bambico FR, Gobbi G. Melancholic-like behaviors and circadian neurobiological abnormalities in melatonin MT1 receptor knockout mice. Int J Neuropsychopharmacol. 2015. Scholar
  111. 111.
    Bersani G, Garavini A. Melatonin add-on in manic patients with treatment resistant insomnia. Prog Neuropsychopharmacol Biol Psychiatry. 2000;24(2):185–91.CrossRefGoogle Scholar
  112. 112.
    Leibenluft E, Feldman-Naim S, Turner EH, Wehr TA, Rosenthal NE. Effects of exogenous melatonin administration and withdrawal in five patients with rapid-cycling bipolar disorder. J Clin Psychiatry. 1997;58(9):383–8.CrossRefGoogle Scholar
  113. 113.
    Zupancic M, Guilleminault C. Agomelatine: a preliminary review of a new antidepressant. CNS Drugs. 2006;20(12):981–92. Scholar
  114. 114.
    Yu YM, Gao KR, Yu H, Shen YF, Li HF. Efficacy and safety of agomelatine vs paroxetine hydrochloride in chinese han patients with major depressive disorder: a multicentre, double-blind, noninferiority, randomized controlled trial. J Clin Psychopharmacol. 2018;38(3):226–33. Scholar
  115. 115.
    Gupta K, Gupta R, Bhatia MS, Tripathi AK, Gupta LK. Effect of agomelatine and fluoxetine on HAM-D score, serum brain-derived neurotrophic factor, and tumor necrosis factor-alpha level in patients with major depressive disorder with severe depression. J Clin Pharmacol. 2017;57(12):1519–26. Scholar
  116. 116.
    Kennedy SH, Avedisova A, Belaidi C, Picarel-Blanchot F, de Bodinat C. Sustained efficacy of agomelatine 10 mg, 25 mg, and 25–50 mg on depressive symptoms and functional outcomes in patients with major depressive disorder. A placebo-controlled study over 6 months. Eur Neuropsychopharmacol. 2016;26(2):378–89. Scholar
  117. 117.
    Fornaro M, McCarthy MJ, De Berardis D, De Pasquale C, Tabaton M, Martino M, et al. Adjunctive agomelatine therapy in the treatment of acute bipolar II depression: a preliminary open label study. Neuropsychiatr Dis Treat. 2013;9:243–51. Scholar
  118. 118.
    Calabrese JR, Guelfi JD, Perdrizet-Chevallier C. Agomelatine adjunctive therapy for acute bipolar depression: preliminary open data. Bipolar Disord. 2007;9(6):628–35. Scholar
  119. 119.
    Yatham LN, Vieta E, Goodwin GM, Bourin M, de Bodinat C, Laredo J, et al. Agomelatine or placebo as adjunctive therapy to a mood stabiliser in bipolar I depression: randomised double-blind placebo-controlled trial. Br J Psychiatry. 2016;208(1):78–86. Scholar
  120. 120.
    McElroy SL, Winstanley EL, Martens B, Patel NC, Mori N, Moeller D, et al. A randomized, placebo-controlled study of adjunctive ramelteon in ambulatory bipolar I disorder with manic symptoms and sleep disturbance. Int Clin Psychopharmacol. 2011;26(1):48–53. Scholar
  121. 121.
    Norris ER, Karen B, Correll JR, Zemanek KJ, Lerman J, Primelo RA, et al. A double-blind, randomized, placebo-controlled trial of adjunctive ramelteon for the treatment of insomnia and mood stability in patients with euthymic bipolar disorder. J Affect Disord. 2013;144(1–2):141–7. Scholar
  122. 122.
    Wang HR, Woo YS, Bahk WM. The role of melatonin and melatonin agonists in counteracting antipsychotic-induced metabolic side effects: a systematic review. Int Clin Psychopharmacol. 2016;31(6):301–6. Scholar
  123. 123.
    Abrahamson EE, Moore RY. Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections. Brain Res. 2001;916(1–2):172–91. Scholar
  124. 124.
    Lee JE, Atkins N Jr, Hatcher NG, Zamdborg L, Gillette MU, Sweedler JV, et al. Endogenous peptide discovery of the rat circadian clock: a focused study of the suprachiasmatic nucleus by ultrahigh performance tandem mass spectrometry. Mol Cell Proteom. 2010;9(2):285–97. Scholar
  125. 125.
    Mieda M. The network mechanism of the central circadian pacemaker of the SCN: do AVP neurons play a more critical role than expected? Front Neurosci. 2019;13:139. Scholar
  126. 126.
    Harrington ME, Hoque S, Hall A, Golombek D, Biello S. Pituitary adenylate cyclase activating peptide phase shifts circadian rhythms in a manner similar to light. J Neurosci. 1999;19(15):6637–42.CrossRefGoogle Scholar
  127. 127.
    Evans JA, Leise TL, Castanon-Cervantes O, Davidson AJ. Dynamic interactions mediated by nonredundant signaling mechanisms couple circadian clock neurons. Neuron. 2013;80(4):973–83. Scholar
  128. 128.
    Aton SJ, Colwell CS, Harmar AJ, Waschek J, Herzog ED. Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat Neurosci. 2005;8(4):476–83. Scholar
  129. 129.
    Harmar AJ, Marston HM, Shen S, Spratt C, West KM, Sheward WJ, et al. The VPAC(2) receptor is essential for circadian function in the mouse suprachiasmatic nuclei. Cell. 2002;109(4):497–508. Scholar
  130. 130.
    Dias BG, Ressler KJ. PACAP and the PAC1 receptor in post-traumatic stress disorder. Neuropsychopharmacology. 2013;38(1):245–6. Scholar
  131. 131.
    Vacic V, McCarthy S, Malhotra D, Murray F, Chou HH, Peoples A, et al. Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature. 2011;471(7339):499–503. Scholar
  132. 132.
    King SB, Lezak KR, O’Reilly M, Toufexis DJ, Falls WA, Braas K, et al. The effects of prior stress on anxiety-like responding to intra-BNST pituitary adenylate cyclase activating polypeptide in male and female rats. Neuropsychopharmacology. 2017;42(8):1679–87. Scholar
  133. 133.
    Ago Y, Condro MC, Tan YV, Ghiani CA, Colwell CS, Cushman JD, et al. Reductions in synaptic proteins and selective alteration of prepulse inhibition in male C57BL/6 mice after postnatal administration of a VIP receptor (VIPR2) agonist. Psychopharmacology (Berl). 2015;232(12):2181–9. Scholar
  134. 134.
    Reed HE, Meyer-Spasche A, Cutler DJ, Coen CW, Piggins HD. Vasoactive intestinal polypeptide (VIP) phase-shifts the rat suprachiasmatic nucleus clock in vitro. Eur J Neurosci. 2001;13(4):839–43.CrossRefGoogle Scholar
  135. 135.
    Li JD, Burton KJ, Zhang C, Hu SB, Zhou QY. Vasopressin receptor V1a regulates circadian rhythms of locomotor activity and expression of clock-controlled genes in the suprachiasmatic nuclei. Am J Physiol Regul Integr Comp Physiol. 2009;296(3):R824–30. Scholar
  136. 136.
    Yamaguchi Y, Suzuki T, Mizoro Y, Kori H, Okada K, Chen Y, et al. Mice genetically deficient in vasopressin V1a and V1b receptors are resistant to jet lag. Science. 2013;342(6154):85–90. Scholar
  137. 137.
    Young LJ, Nilsen R, Waymire KG, MacGregor GR, Insel TR. Increased affiliative response to vasopressin in mice expressing the V1a receptor from a monogamous vole. Nature. 1999;400(6746):766–8. Scholar
  138. 138.
    Zhou JN, Riemersma RF, Unmehopa UA, Hoogendijk WJ, van Heerikhuize JJ, Hofman MA, et al. Alterations in arginine vasopressin neurons in the suprachiasmatic nucleus in depression. Arch Gen Psychiatry. 2001;58(7):655–62.CrossRefGoogle Scholar
  139. 139.
    Mori K, Miyazato M, Ida T, Murakami N, Serino R, Ueta Y, et al. Identification of neuromedin S and its possible role in the mammalian circadian oscillator system. Embo J. 2005;24(2):325–35. Scholar
  140. 140.
    Ida T, Mori K, Miyazato M, Egi Y, Abe S, Nakahara K, et al. Neuromedin s is a novel anorexigenic hormone. Endocrinology. 2005;146(10):4217–23. Scholar
  141. 141.
    Sakamoto T, Mori K, Miyazato M, Kangawa K, Sameshima H, Nakahara K, et al. Involvement of neuromedin S in the oxytocin release response to suckling stimulus. Biochem Biophys Res Commun. 2008;375(1):49–53. Scholar
  142. 142.
    Lee IT, Chang AS, Manandhar M, Shan Y, Fan J, Izumo M, et al. Neuromedin s-producing neurons act as essential pacemakers in the suprachiasmatic nucleus to couple clock neurons and dictate circadian rhythms. Neuron. 2015;85(5):1086–102. Scholar
  143. 143.
    Mitchell JD, Maguire JJ, Davenport AP. Emerging pharmacology and physiology of neuromedin U and the structurally related peptide neuromedin S. Br J Pharmacol. 2009;158(1):87–103. Scholar
  144. 144.
    Romanov RA, Zeisel A, Bakker J, Girach F, Hellysaz A, Tomer R, et al. Molecular interrogation of hypothalamic organization reveals distinct dopamine neuronal subtypes. Nat Neurosci. 2017;20(2):176–88. Scholar
  145. 145.
    Dulcis D, Jamshidi P, Leutgeb S, Spitzer NC. Neurotransmitter switching in the adult brain regulates behavior. Science. 2013;340(6131):449–53. Scholar
  146. 146.
    Aumann TD. Environment- and activity-dependent dopamine neurotransmitter plasticity in the adult substantia nigra. J Chem Neuroanat. 2016;73:21–32. Scholar
  147. 147.
    Zhou M, Rebholz H, Brocia C, Warner-Schmidt JL, Fienberg AA, Nairn AC, et al. Forebrain overexpression of CK1delta leads to down-regulation of dopamine receptors and altered locomotor activity reminiscent of ADHD. Proc Natl Acad Sci USA. 2010;107(9):4401–6. Scholar
  148. 148.
    Walton KM, Fisher K, Rubitski D, Marconi M, Meng QJ, Sladek M, et al. Selective inhibition of casein kinase 1 epsilon minimally alters circadian clock period. J Pharmacol Exp Ther. 2009;330(2):430–9. Scholar
  149. 149.
    Isojima Y, Nakajima M, Ukai H, Fujishima H, Yamada RG, Masumoto KH, et al. CKIepsilon/delta-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock. Proc Natl Acad Sci USA. 2009;106(37):15744–9. Scholar
  150. 150.
    Meng QJ, Maywood ES, Bechtold DA, Lu WQ, Li J, Gibbs JE, et al. Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes. Proc Natl Acad Sci USA. 2010;107(34):15240–5. Scholar
  151. 151.
    Li D, Herrera S, Bubula N, Nikitina E, Palmer AA, Hanck DA, et al. Casein kinase 1 enables nucleus accumbens amphetamine-induced locomotion by regulating AMPA receptor phosphorylation. J Neurochem. 2011;118(2):237–47. Scholar
  152. 152.
    Arey R, McClung CA. An inhibitor of casein kinase 1 epsilon/delta partially normalizes the manic-like behaviors of the ClockDelta19 mouse. Behav Pharmacol. 2012;23(4):392–6. Scholar
  153. 153.
    Cho H, Zhao X, Hatori M, Yu RT, Barish GD, Lam MT, et al. Regulation of circadian behaviour and metabolism by REV-ERB-alpha and REV-ERB-beta. Nature. 2012;485(7396):123–7. Scholar
  154. 154.
    Chung S, Lee EJ, Yun S, Choe HK, Park SB, Son HJ, et al. Impact of circadian nuclear receptor REV-ERBalpha on midbrain dopamine production and mood regulation. Cell. 2014;157(4):858–68. Scholar
  155. 155.
    McCarthy MJ, Nievergelt CM, Shekhtman T, Kripke DF, Welsh DK, Kelsoe JR. Functional genetic variation in the Rev-Erbalpha pathway and lithium response in the treatment of bipolar disorder. Genes Brain Behav. 2011;10(8):852–61. Scholar
  156. 156.
    Stehlin-Gaon C, Willmann D, Zeyer D, Sanglier S, Van Dorsselaer A, Renaud JP, et al. All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta. Nat Struct Biol. 2003;10(10):820–5. Scholar
  157. 157.
    Hu X, Wang Y, Hao LY, Liu X, Lesch CA, Sanchez BM, et al. Sterol metabolism controls T(H)17 differentiation by generating endogenous RORgamma agonists. Nat Chem Biol. 2015;11(2):141–7. Scholar
  158. 158.
    Solt LA, Wang Y, Banerjee S, Hughes T, Kojetin DJ, Lundasen T, et al. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature. 2012;485(7396):62–8. Scholar
  159. 159.
    He B, Nohara K, Park N, Park YS, Guillory B, Zhao Z, et al. The small molecule nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome. Cell Metab. 2016;23(4):610–21. Scholar
  160. 160.
    Banerjee S, Wang Y, Solt LA, Griffett K, Kazantzis M, Amador A, et al. Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour. Nat Commun. 2014;5:5759. Scholar
  161. 161.
    Dierickx P, Emmett MJ, Jiang C, Uehara K, Liu M, Adlanmerini M, et al. SR9009 has REV-ERB-independent effects on cell proliferation and metabolism. Proc Natl Acad Sci USA. 2019;116(25):12147–52. Scholar
  162. 162.
    Wei H, Landgraf D, Wang G, McCarthy MJ. Inositol polyphosphates contribute to cellular circadian rhythms: Implications for understanding lithium’s molecular mechanism. Cell Signal. 2018;44:82–91. Scholar
  163. 163.
    Landgraf D, Joiner WJ, McCarthy MJ, Kiessling S, Barandas R, Young JW, et al. The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms. Neuropharmacology. 2016;107:262–70. Scholar
  164. 164.
    Kozikowski AP, Gunosewoyo H, Guo S, Gaisina IN, Walter RL, Ketcherside A, et al. Identification of a glycogen synthase kinase-3beta inhibitor that attenuates hyperactivity in CLOCK mutant mice. ChemMedChem. 2011;6(9):1593–602. Scholar
  165. 165.
    Bhat RV, Andersson U, Andersson S, Knerr L, Bauer U, Sundgren-Andersson AK. The conundrum of GSK3 inhibitors: is it the dawn of a new beginning? J Alzheimers Dis. 2018;64(s1):S547–54. Scholar
  166. 166.
    Hirota T, Lee JW, St John PC, Sawa M, Iwaisako K, Noguchi T, et al. Identification of small molecule activators of cryptochrome. Science. 2012;337(6098):1094–7. Scholar
  167. 167.
    Lee JW, Hirota T, Kumar A, Kim NJ, Irle S, Kay SA. Development of small-molecule cryptochrome stabilizer derivatives as modulators of the circadian clock. ChemMedChem. 2015;10(9):1489–97. Scholar
  168. 168.
    Zhang EE, Liu Y, Dentin R, Pongsawakul PY, Liu AC, Hirota T, et al. Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nat Med. 2010;16(10):1152–6. Scholar
  169. 169.
    Jang J, Chung S, Choi Y, Lim HY, Son Y, Chun SK, et al. The cryptochrome inhibitor KS15 enhances E-box-mediated transcription by disrupting the feedback action of a circadian transcription-repressor complex. Life Sci. 2018;200:49–55. Scholar
  170. 170.
    Yoo SH, Mohawk JA, Siepka SM, Shan Y, Huh SK, Hong HK, et al. Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm. Cell. 2013;152(5):1091–105. Scholar
  171. 171.
    Landre V, Rotblat B, Melino S, Bernassola F, Melino G. Screening for E3-ubiquitin ligase inhibitors: challenges and opportunities. Oncotarget. 2014;5(18):7988–8013. Scholar
  172. 172.
    Jones KA, Hatori M, Mure LS, Bramley JR, Artymyshyn R, Hong SP, et al. Small-molecule antagonists of melanopsin-mediated phototransduction. Nat Chem Biol. 2013;9(10):630–5. Scholar
  173. 173.
    Keenan WT, Fernandez DC, Shumway LJ, Zhao H, Hattar S. Eye-drops for activation of DREADDs. Front Neural Circuits. 2017;11:93. Scholar
  174. 174.
    De Silva SR, Barnard AR, Hughes S, Tam SKE, Martin C, Singh MS, et al. Long-term restoration of visual function in end-stage retinal degeneration using subretinal human melanopsin gene therapy. Proc Natl Acad Sci USA. 2017;114(42):11211–6. Scholar
  175. 175.
    Vogt A, Cooley KA, Brisson M, Tarpley MG, Wipf P, Lazo JS. Cell-active dual specificity phosphatase inhibitors identified by high-content screening. Chem Biol. 2003;10(8):733–42.CrossRefGoogle Scholar
  176. 176.
    Chakraborty A, Latapy C, Xu J, Snyder SH, Beaulieu JM. Inositol hexakisphosphate kinase-1 regulates behavioral responses via GSK3 signaling pathways. Mol Psychiatry. 2014;19(3):284–93. Scholar
  177. 177.
    Dijk DJ, Duffy JF, Czeisler CA. Circadian and sleep/wake dependent aspects of subjective alertness and cognitive performance. J Sleep Res. 1992;1(2):112–7.CrossRefGoogle Scholar
  178. 178.
    Czeisler CA, Duffy JF, Shanahan TL, Brown EN, Mitchell JF, Rimmer DW, et al. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science. 1999;284(5423):2177–81.CrossRefGoogle Scholar
  179. 179.
    Moon JH, Cho CH, Son GH, Geum D, Chung S, Kim H, et al. Advanced circadian phase in mania and delayed circadian phase in mixed mania and depression returned to normal after treatment of bipolar disorder. EBioMedicine. 2016;11:285–95. Scholar
  180. 180.
    Lane JM, Vlasac I, Anderson SG, Kyle SD, Dixon WG, Bechtold DA, et al. Genome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UK Biobank. Nat Commun. 2016;7:10889. Scholar
  181. 181.
    Anafi RC, Francey LJ, Hogenesch JB, Kim J. CYCLOPS reveals human transcriptional rhythms in health and disease. Proc Natl Acad Sci USA. 2017;114(20):5312–7. Scholar
  182. 182.
    Braun R, Kath WL, Iwanaszko M, Kula-Eversole E, Abbott SM, Reid KJ, et al. Universal method for robust detection of circadian state from gene expression. Proc Natl Acad Sci USA. 2018;115(39):E9247–56. Scholar
  183. 183.
    Wu G, Ruben MD, Schmidt RE, Francey LJ, Smith DF, Anafi RC, et al. Population-level rhythms in human skin with implications for circadian medicine. Proc Natl Acad Sci USA. 2018;115(48):12313–8. Scholar
  184. 184.
    Lockley SW, Dressman MA, Licamele L, Xiao C, Fisher DM, Flynn-Evans EE, et al. Tasimelteon for non-24-hour sleep-wake disorder in totally blind people (SET and RESET): two multicentre, randomised, double-masked, placebo-controlled phase 3 trials. Lancet. 2015;386(10005):1754–64. Scholar
  185. 185.
    Anderson P. FDA panel gives nod to circadian rhythm disorder drug. Medscape. 2013.Google Scholar

Copyright information

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

Authors and Affiliations

  1. 1.Department of Psychiatry and Center for Circadian BiologyUniversity of California San DiegoLa JollaUSA
  2. 2.Psychiatry ServiceVA San Diego Healthcare SystemSan DiegoUSA
  3. 3.Department of PsychiatryPenn State Health Milton S. Hershey Medical CenterHersheyUSA

Personalised recommendations