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

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Abstract

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.

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References

  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. https://doi.org/10.1001/archgenpsychiatry.2011.12.

    Article  PubMed  PubMed Central  Google Scholar 

  2. McCarthy MJ, Welsh DK. Cellular circadian clocks in mood disorders. J Biol Rhythms. 2012;27(5):339–52. https://doi.org/10.1177/0748730412456367.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s11920-014-0483-7.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1080/07420528.2018.1487975.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1038/tp.2016.242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Malhi GS, Fritz K, Elangovan P, Irwin L. Mixed States: modelling and management. CNS Drugs. 2019;33(4):301–13. https://doi.org/10.1007/s40263-019-00609-3.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1186/s40345-017-0113-5.

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1097/YPG.0000000000000215.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1001/archpsyc.62.9.996.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.neubiorev.2012.12.009.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1080/07420520500545979.

    Article  PubMed  Google Scholar 

  12. Mohawk JA, Green CB, Takahashi JS. Central and peripheral circadian clocks in mammals. Annu Rev Neurosci. 2012;35:445–62. https://doi.org/10.1146/annurev-neuro-060909-153128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Welsh DK, Takahashi JS, Kay SA. Suprachiasmatic nucleus: cell autonomy and network properties. Annu Rev Physiol. 2010;72:551–77. https://doi.org/10.1146/annurev-physiol-021909-135919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schmidt TM, Chen SK, Hattar S. Intrinsically photosensitive retinal ganglion cells: many subtypes, diverse functions. Trends Neurosci. 2011;34(11):572–80. https://doi.org/10.1016/j.tins.2011.07.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.biopsych.2016.03.1050.

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1111/ejn.14343.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nrn3743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.cell.2018.08.004 (e18).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/nature11673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/mp.2014.167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.1407935111.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.biopsych.2014.07.030.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.biopsych.2010.04.031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.0609625104.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1126/science.aao0318.

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1111/ejn.13085.

    Article  PubMed  Google Scholar 

  28. Freyberg Z, McCarthy MJ. Dopamine D2 receptors and the circadian clock reciprocally mediate antipsychotic drug-induced metabolic disturbances. NPJ Schizophr. 2017;3:17. https://doi.org/10.1038/s41537-017-0018-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1007/s11920-015-0637-2.

    Article  PubMed  Google Scholar 

  30. Partch CL, Green CB, Takahashi JS. Molecular architecture of the mammalian circadian clock. Trends Cell Biol. 2014;24(2):90–9. https://doi.org/10.1016/j.tcb.2013.07.002.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1074/jbc.M506225200.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1126/science.1121613.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1371/journal.pone.0008561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1074/jbc.M503526200.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1074/jbc.RA117.000773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1111/j.1356-9597.2004.00758.x.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  38. Berridge MJ, Downes CP, Hanley MR. Neural and developmental actions of lithium: a unifying hypothesis. Cell. 1989;59(3):411–9.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1073/pnas.0811410106.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  42. Kripke DF, Wyborney VG. Lithium slows rat circadian activity rhythms. Life Sci. 1980;26(16):1319–21.

    Article  CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  44. Welsh DK, Moore-Ede MC. Lithium lengthens circadian period in a diurnal primate, Saimiri sciureus. Biol Psychiatry. 1990;28(2):117–26.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1038/tp.2013.90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Abe M, Herzog ED, Block GD. Lithium lengthens the circadian period of individual suprachiasmatic nucleus neurons. Neuroreport. 2000;11(14):3261–4.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.euroneuro.2016.05.003.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.neuropharm.2015.10.017.

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.3109/07420528.2015.1062024.

    Article  CAS  PubMed  Google Scholar 

  50. Harvey AG. Sleep and circadian rhythms in bipolar disorder: seeking synchrony, harmony, and regulation. Am J Psychiatry. 2008;165(7):820–9. https://doi.org/10.1176/appi.ajp.2008.08010098.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1176/appi.ajp.162.1.50.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.jad.2009.05.022.

    Article  PubMed  Google Scholar 

  53. Jackson A, Cavanagh J, Scott J. A systematic review of manic and depressive prodromes. J Affect Disord. 2003;74(3):209–17.

    Article  Google Scholar 

  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. https://doi.org/10.1016/j.jad.2009.10.003.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1111/j.1399-5618.2008.00533.x.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.jbtep.2009.11.007.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1111/j.1365-2869.2010.00826.x.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.jad.2008.06.028.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1111/j.1399-5618.2005.00187.x.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.4088/JCP.13m08506.

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.jad.2014.04.034.

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.1513525113.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/S2215-0366(18)30139-1.

    Article  PubMed  Google Scholar 

  66. Teicher MH. Actigraphy and motion analysis: new tools for psychiatry. Harv Rev Psychiatry. 1995;3(1):18–35.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1038/ncomms10448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1371/journal.pgen.1006125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.psychres.2008.03.003.

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1111/j.1399-5618.2007.00573.x.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1081/CBI-200062413.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1530/JOE-14-0141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kripke DF, Elliott JA, Welsh DK, Youngstedt SD. Photoperiodic and circadian bifurcation theories of depression and mania. F1000Res. 2015;4:107. https://doi.org/10.12688/f1000research.6444.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1186/1471-244X-3-6.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Cassidy F, Carroll BJ. Seasonal variation of mixed and pure episodes of bipolar disorder. J Affect Disord. 2002;68(1):25–31.

    Article  Google Scholar 

  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. https://doi.org/10.1192/bjp.167.1.58.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.jad.2004.11.010.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1177/0004867415598844.

    Article  PubMed  Google Scholar 

  82. Macchi MM, Bruce JN. Human pineal physiology and functional significance of melatonin. Front Neuroendocrinol. 2004;25(3–4):177–95. https://doi.org/10.1016/j.yfrne.2004.08.001.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1006/frne.2000.0202.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.eurpsy.2013.04.001.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.psychres.2019.05.025.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.psychres.2013.05.023.

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1111/ejn.12602.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.psc.2005.01.005.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.psyneuen.2015.10.014.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1210/jcem-61-3-429.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.psyneuen.2018.01.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1371/journal.pbio.1000559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.4088/jcp.17m11565.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1038/3695.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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. https://doi.org/10.1523/JNEUROSCI.3820-09.2009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1177/0748730414540453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1177/074873000129001404.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1002/hup.2533.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.mce.2012.01.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1074/jbc.271.23.13515.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1503/jpn.130009.

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.phrs.2019.04.015.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1093/ijnp/pyu075.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Bersani G, Garavini A. Melatonin add-on in manic patients with treatment resistant insomnia. Prog Neuropsychopharmacol Biol Psychiatry. 2000;24(2):185–91.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  113. Zupancic M, Guilleminault C. Agomelatine: a preliminary review of a new antidepressant. CNS Drugs. 2006;20(12):981–92. https://doi.org/10.2165/00023210-200620120-00003.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1097/JCP.0000000000000878.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1002/jcph.963.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.euroneuro.2015.09.006.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.2147/NDT.S41557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1111/j.1399-5618.2007.00507.x.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1192/bjp.bp.114.147587.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1097/YIC.0b013e3283400d35.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.jad.2012.06.023.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1097/YIC.0000000000000135.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/s0006-8993(01)02890-6.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1074/mcp.M900362-MCP200.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.3389/fnins.2019.00139.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.neuron.2013.08.022.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nn1419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/s0092-8674(02)00736-5.

    Article  CAS  PubMed  Google Scholar 

  130. Dias BG, Ressler KJ. PACAP and the PAC1 receptor in post-traumatic stress disorder. Neuropsychopharmacology. 2013;38(1):245–6. https://doi.org/10.1038/npp.2012.147.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nature09884.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/npp.2017.16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1007/s00213-014-3848-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1152/ajpregu.90463.2008.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1126/science.1238599.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/23475.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1038/sj.emboj.7600526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1210/en.2005-0107.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.bbrc.2008.07.124.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.neuron.2015.02.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1111/j.1476-5381.2009.00252.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/nn.4462.

    Article  CAS  PubMed  Google Scholar 

  145. Dulcis D, Jamshidi P, Leutgeb S, Spitzer NC. Neurotransmitter switching in the adult brain regulates behavior. Science. 2013;340(6131):449–53. https://doi.org/10.1126/science.1234152.

    Article  CAS  PubMed  Google Scholar 

  146. Aumann TD. Environment- and activity-dependent dopamine neurotransmitter plasticity in the adult substantia nigra. J Chem Neuroanat. 2016;73:21–32. https://doi.org/10.1016/j.jchemneu.2015.12.009.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1073/pnas.0915173107.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1124/jpet.109.151415.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1073/pnas.0908733106.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1073/pnas.1005101107.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1111/j.1471-4159.2011.07308.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1097/FBP.0b013e32835651fd.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/nature11048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.cell.2014.03.039.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1111/j.1601-183X.2011.00725.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/nsb979.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nchembio.1714.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nature11030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.cmet.2016.03.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/ncomms6759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.1904226116.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.cellsig.2018.01.001.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.neuropharm.2016.03.047.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1002/cmdc.201100188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.3233/JAD-179934.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1126/science.1223710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1002/cmdc.201500260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/nm.2214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.lfs.2018.03.022.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.cell.2013.01.055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.18632/oncotarget.2431.

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/nchembio.1333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Keenan WT, Fernandez DC, Shumway LJ, Zhao H, Hattar S. Eye-drops for activation of DREADDs. Front Neural Circuits. 2017;11:93. https://doi.org/10.3389/fncir.2017.00093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.1701589114.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1038/mp.2013.21.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.ebiom.2016.08.019.

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/ncomms10889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.1619320114.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1073/pnas.1800314115.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1073/pnas.1809442115.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/S0140-6736(15)60031-9.

    Article  CAS  PubMed  Google Scholar 

  185. Anderson P. FDA panel gives nod to circadian rhythm disorder drug. Medscape. 2013.

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Authors and Affiliations

  1. Department of Psychiatry and Center for Circadian Biology, University of California San Diego, La Jolla, CA, 92093, USA

    Alessandra Porcu & Michael J. McCarthy

  2. Psychiatry Service, VA San Diego Healthcare System, 3350 La Jolla Village Dr MC116A, San Diego, CA, 92161, USA

    Michael J. McCarthy

  3. Department of Psychiatry, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, 17033-0850, USA

    Robert Gonzalez

Authors
  1. Alessandra Porcu
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  2. Robert Gonzalez
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  3. Michael J. McCarthy
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Corresponding author

Correspondence to Michael J. McCarthy.

Ethics declarations

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

Funding

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.

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Porcu, A., Gonzalez, R. & McCarthy, M.J. Pharmacological Manipulation of the Circadian Clock: A Possible Approach to the Management of Bipolar Disorder. CNS Drugs 33, 981–999 (2019). https://doi.org/10.1007/s40263-019-00673-9

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