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Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder

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Abstract

Conventional antidepressants require 2–8 weeks for a full clinical response. In contrast, two rapidly acting antidepressant interventions, low-dose ketamine and sleep deprivation (SD) therapy, act within hours to robustly decrease depressive symptoms in a subgroup of major depressive disorder (MDD) patients. Evidence that MDD may be a circadian-related illness is based, in part, on a large set of clinical data showing that diurnal rhythmicity (sleep, temperature, mood and hormone secretion) is altered during depressive episodes. In a microarray study, we observed widespread changes in cyclic gene expression in six regions of postmortem brain tissue of depressed patients matched with controls for time-of-death (TOD). We screened 12 000 transcripts and observed that the core clock genes, essential for controlling virtually all rhythms in the body, showed robust 24-h sinusoidal expression patterns in six brain regions in control subjects. In MDD patients matched for TOD with controls, the expression patterns of the clock genes in brain were significantly dysregulated. Some of the most robust changes were seen in anterior cingulate (ACC). These findings suggest that in addition to structural abnormalities, lesion studies, and the large body of functional brain imaging studies reporting increased activation in the ACC of depressed patients who respond to a wide range of therapies, there may be a circadian dysregulation in clock gene expression in a subgroup of MDDs. Here, we review human, animal and neuronal cell culture data suggesting that both low-dose ketamine and SD can modulate circadian rhythms. We hypothesize that the rapid antidepressant actions of ketamine and SD may act, in part, to reset abnormal clock genes in MDD to restore and stabilize circadian rhythmicity. Conversely, clinical relapse may reflect a desynchronization of the clock, indicative of a reactivation of abnormal clock gene function. Future work could involve identifying specific small molecules capable of resetting and stabilizing clock genes to evaluate if they can rapidly relieve symptoms and sustain improvement.

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References

  1. Masri S, Sassone-Corsi P . The circadian clock: a framework linking metabolism, epigenetics and neuronal function. Nat Rev Neurosci 2013; 14: 69–75.

    Article  CAS  PubMed  Google Scholar 

  2. Edgar N, McClung CA . Major depressive disorder: a loss of circadian synchrony?. Bioessays 2013; 35: 940–944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hasler BP, Buysse DJ, Kupfer DJ, Germain A . Phase relationships between core body temperature, melatonin, and sleep are associated with depression severity: further evidence for circadian misalignment in non-seasonal depression. Psychiatry Res 2010; 178: 205–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bunney BG, Bunney WE . Rapid-acting antidepressant strategies: mechanisms of action. Int J Neuropsychopharmacol 2012; 15: 695–713.

    Article  CAS  PubMed  Google Scholar 

  5. Insel TR, Wang PS . The STAR*D trial: revealing the need for better treatments. Psychiatr Serv 2009; 60: 1466–1467.

    Article  PubMed  Google Scholar 

  6. Rush AJ, Trivedi M, Fava M . Depression, IV: STAR*D treatment trial for depression. Am J Psychiatry 2003; 160: 237.

    Article  PubMed  Google Scholar 

  7. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000; 47: 351–354.

    Article  CAS  PubMed  Google Scholar 

  8. Mathews DC, Zarate CA Jr . Current status of ketamine and related compounds for depression. J Clin Psychiatry 2013; 74: 516–517.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wu JC, Bunney WE . The biological basis of an antidepressant response to sleep deprivation and relapse: review and hypothesis. Am J Psychiatry 1990; 147: 14–21.

    Article  CAS  PubMed  Google Scholar 

  10. Benedetti F, Barbini B, Colombo C, Smeraldi E . Chronotherapeutics in a psychiatric ward. Sleep Med Rev 2007; 11: 509–522.

    Article  PubMed  Google Scholar 

  11. Zunszain PA, Horowitz MA, Cattaneo A, Lupi MM, Pariante CM . Ketamine: synaptogenesis, immunomodulation and glycogen synthase kinase-3 as underlying mechanisms of its antidepressant properties. Mol Psychiatry 2013; 18: 1236–1241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dijk DJ, Duffy JF, Silva EJ, Shanahan TL, Boivin DB, Czeisler CA . Amplitude reduction and phase shifts of melatonin, cortisol and other circadian rhythms after a gradual advance of sleep and light exposure in humans. PLoS One 2012; 7: e30037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fisher SP, Foster RG, Peirson SN . The circadian control of sleep. Handb Exp Pharmacol 2013; 217: 157–183.

    Article  CAS  Google Scholar 

  14. Franken P, Dijk DJ . Circadian clock genes and sleep homeostasis. Eur J Neurosci 2009; 29: 1820–1829.

    Article  CAS  PubMed  Google Scholar 

  15. Borbely AA, Tobler I . Manifestations and functional implications of sleep homeostasis. Handb Clin Neurol 2011; 98: 205–213.

    Article  PubMed  Google Scholar 

  16. Mendlewicz J . Sleep disturbances: core symptoms of major depressive disorder rather than associated or comorbid disorders. World J Biol Psychiatry 2009; 10: 269–275.

    Article  PubMed  Google Scholar 

  17. Ohayon MM . Insomnia: a ticking clock for depression?. J Psychiatr Res 2007; 41: 893–894.

    Article  PubMed  Google Scholar 

  18. Germain A, Kupfer DJ . Circadian rhythm disturbances in depression. Hum Psychopharmacol 2008; 23: 571–585.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Franzen PL, Buysse DJ . Sleep disturbances and depression: risk relationships for subsequent depression and therapeutic implications. Dialogues Clin Neurosci 2008; 10: 473–481.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Chang PP, Ford DE, Mead LA, Cooper-Patrick L, Klag MJ . Insomnia in young men and subsequent depression. The Johns Hopkins Precursors Study. Am J Epidemiol 1997; 146: 105–114.

    Article  CAS  PubMed  Google Scholar 

  21. Pigeon WR, Pinquart M, Conner K . Meta-analysis of sleep disturbance and suicidal thoughts and behaviors. J Clin Psychiatry 2012; 73: e1160–e1167.

    Article  PubMed  Google Scholar 

  22. Kupfer DJ, Foster FG, Reich L, Thompson SK, Weiss B . EEG sleep changes as predictors in depression. Am J Psychiatry 1976; 133: 622–626.

    Article  CAS  PubMed  Google Scholar 

  23. Troxel WM, Kupfer DJ, Reynolds CF 3rd, Frank E, Thase ME, Miewald JM et al. Insomnia and objectively measured sleep disturbances predict treatment outcome in depressed patients treated with psychotherapy or psychotherapy-pharmacotherapy combinations. J Clin Psychiatry 2012; 73: 478–485.

    Article  PubMed  Google Scholar 

  24. Buysse DJ, Monk TH, Kupfer DJ, Frank E, Stapf D . Circadian patterns of unintended sleep episodes during a constant routine in remitted depressed patients. J Psychiatr Res 1995; 29: 407–416.

    Article  CAS  PubMed  Google Scholar 

  25. Murray G . Diurnal mood variation in depression: a signal of disturbed circadian function?. J Affect Disord 2007; 102: 47–53.

    Article  PubMed  Google Scholar 

  26. Wirz-Justice A . Diurnal variation of depressive symptoms. Dialogues Clin Neurosci 2008; 10: 337–343.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Saini C, Morf J, Stratmann M, Gos P, Schibler U . Simulated body temperature rhythms reveal the phase-shifting behavior and plasticity of mammalian circadian oscillators. Genes Dev 2012; 26: 567–580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Avery DH, Shah SH, Eder DN, Wildschiodtz G . Nocturnal sweating and temperature in depression. Acta Psychiatr Scand 1999; 100: 295–301.

    Article  CAS  PubMed  Google Scholar 

  29. Elsenga S, Van den Hoofdakker RH . Body core temperature and depression during total sleep deprivation in depressives. Biol Psychiatry 1988; 24: 531–540.

    Article  CAS  PubMed  Google Scholar 

  30. Souetre E, Salvati E, Wehr TA, Sack DA, Krebs B, Darcourt G . Twenty-four-hour profiles of body temperature and plasma TSH in bipolar patients during depression and during remission and in normal control subjects. Am J Psychiatry 1988; 145: 1133–1137.

    Article  CAS  PubMed  Google Scholar 

  31. Keller J, Flores B, Gomez RG, Solvason HB, Kenna H, Williams GH et al. Cortisol circadian rhythm alterations in psychotic major depression. Biol Psychiatry 2006; 60: 275–281.

    Article  CAS  PubMed  Google Scholar 

  32. Holsboer F . The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 2000; 23: 477–501.

    Article  CAS  PubMed  Google Scholar 

  33. Banki CM, Bissette G, Arato M, O'Connor L, Nemeroff CB . CSF corticotropin-releasing factor-like immunoreactivity in depression and schizophrenia. Am J Psychiatry 1987; 144: 873–877.

    Article  CAS  PubMed  Google Scholar 

  34. Bunney WE Jr., Fawcett JA, Davis JM, Gifford S . Further evaluation of urinary 17-hydroxycorticosteroids in suicidal patients. Arch Gen Psychiatry 1969; 21: 138–150.

    Article  PubMed  Google Scholar 

  35. Carpenter WT Jr., Bunney WE Jr . Adrenal cortical activity in depressive illness. Am J Psychiatry 1971; 128: 31–40.

    Article  PubMed  Google Scholar 

  36. Scharnholz B, Lederbogen F, Feuerhack A, Bach A, Kopf D, Frankhauser P et al. Does night-time cortisol excretion normalize in the long-term course of depression?. Pharmacopsychiatry 2010; 43: 161–165.

    Article  CAS  PubMed  Google Scholar 

  37. Vreeburg SA, Hoogendijk WJ, van Pelt J, Derijk RH, Verhagen JC, van Dyck R et al. Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: results from a large cohort study. Arch Gen Psychiatry 2009; 66: 617–626.

    Article  CAS  PubMed  Google Scholar 

  38. Lewy AJ . Depressive disorders may more commonly be related to circadian phase delays rather than advances: time will tell. Sleep Med 2010; 11: 117–118.

    Article  PubMed  Google Scholar 

  39. Buckley TM, Schatzberg AF . A pilot study of the phase angle between cortisol and melatonin in major depression—a potential biomarker?. J Psychiatr Res 2010; 44: 69–74.

    Article  PubMed  Google Scholar 

  40. Khaleghipour S, Masjedi M, Ahade H, Enayate M, Pasha G, Nadery F et al. Morning and nocturnal serum melatonin rhythm levels in patients with major depressive disorder: an analytical cross-sectional study. Sao Paulo Med J 2012; 130: 167–172.

    Article  PubMed  Google Scholar 

  41. 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: 412–416.

    Article  CAS  PubMed  Google Scholar 

  42. Lamont EW, Coutu DL, Cermakian N, Boivin DB . Circadian rhythms and clock genes in psychotic disorders. Isr J Psychiatry Relat Sci 2010; 47: 27–35.

    PubMed  Google Scholar 

  43. Zanini M, Castro J, Coelho FM, Bittencourt L, Bressan RA, Tufik S et al. Do sleep abnormalities and misaligned sleep/circadian rhythm patterns represent early clinical characteristics for developing psychosis in high risk populations?. Neurosci Biobehav Rev 2013; 37: 2631–2637.

    Article  PubMed  Google Scholar 

  44. 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: e317–e322.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Morin LP . Neuroanatomy of the extended circadian rhythm system. Exp Neurol 2013; 243: 4–20.

    Article  PubMed  Google Scholar 

  46. McCarthy MJ, Welsh DK . Cellular circadian clocks in mood disorders. J Biol Rhythms 2012; 27: 339–352.

    Article  CAS  PubMed  Google Scholar 

  47. Salomon RM, Cowan RL . Oscillatory serotonin function in depression. Synapse 2013; 67: 801–820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. van Oosterhout F, Lucassen EA, Houben T, vanderLeest HT, Antle MC, Meijer JH . Amplitude of the SCN clock enhanced by the behavioral activity rhythm. PLoS One 2012; 7: e39693.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Mistlberger RE, Antle MC . Entrainment of circadian clocks in mammals by arousal and food. Essays Biochem 2011; 49: 119–136.

    Article  CAS  PubMed  Google Scholar 

  50. Sahar S, Sassone-Corsi P . The epigenetic language of circadian clocks. Handb Exp Pharmacol 2013; (217: 29–44.

    Article  CAS  Google Scholar 

  51. Shearman LP, Sriram S, Weaver DR, Maywood ES, Chaves I, Zheng B et al. Interacting molecular loops in the mammalian circadian clock. Science 2000; 288: 1013–1019.

    Article  CAS  PubMed  Google Scholar 

  52. Mohawk JA, Green CB, Takahashi JS . Central and peripheral circadian clocks in mammals. Annu Rev Neurosci 2012; 35: 445–462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Partch CL, Green CB, Takahashi JS . Molecular architecture of the mammalian circadian clock. Trends Cell Biol 2014; 24: 90–99.

    Article  CAS  PubMed  Google Scholar 

  54. Wu YH, Fischer DF, Kalsbeek A, Garidou-Boof ML, van der Vliet J, van Heijningen C et al. Pineal clock gene oscillation is disturbed in Alzheimer's disease, due to functional disconnection from the ‘master clock’. FASEB J 2006; 20: 1874–1876.

    Article  CAS  PubMed  Google Scholar 

  55. Ackermann K, Dehghani F, Bux R, Kauert G, Stehle JH . Day-night expression patterns of clock genes in the human pineal gland. J Pineal Res 2007; 43: 185–194.

    Article  CAS  PubMed  Google Scholar 

  56. Wunderer F, Kuhne S, Jilg A, Ackermann K, Sebesteny T, Maronde E et al. Clock gene expression in the human pituitary gland. Endocrinology 2013; 154: 2046–2057.

    Article  CAS  PubMed  Google Scholar 

  57. Sequeira A, Morgan L, Walsh DM, Cartagena PM, Choudary P, Li J et al. Gene expression changes in the prefrontal cortex, anterior cingulate cortex and nucleus accumbens of mood disorders subjects that committed suicide. PLoS One 2012; 7: e35367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Li JZ, Bunney BG, Meng F, Hagenauer MH, Walsh DM, Vawter MP et al. Circadian patterns of gene expression in the human brain and disruption in major depressive disorder. Proc Natl Acad Sci USA 2013; 110: 9950–9955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Dunlap JC . Molecular bases for circadian clocks. Cell 1999; 96: 271–290.

    Article  CAS  PubMed  Google Scholar 

  60. Drevets WC, Savitz J, Trimble M . The subgenual anterior cingulate cortex in mood disorders. CNS spectrums 2008; 13: 663–681.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C et al. Deep brain stimulation for treatment-resistant depression. Neuron 2005; 45: 651–660.

    Article  CAS  PubMed  Google Scholar 

  62. Gotlib IH, Sivers H, Gabrieli JD, Whitfield-Gabrieli S, Goldin P, Minor KL et al. Subgenual anterior cingulate activation to valenced emotional stimuli in major depression. Neuroreport 2005; 16: 1731–1734.

    Article  PubMed  Google Scholar 

  63. Salvadore G, Cornwell BR, Colon-Rosario V, Coppola R, Grillon C, Zarate CA Jr. et al. Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological biomarker that predicts rapid antidepressant response to ketamine. Biol Psychiatry 2009; 65: 289–295.

    Article  CAS  PubMed  Google Scholar 

  64. Pizzagalli D, Pascual-Marqui RD, Nitschke JB, Oakes TR, Larson CL, Abercrombie HC et al. Anterior cingulate activity as a predictor of degree of treatment response in major depression: evidence from brain electrical tomography analysis. Am J Psychiatry 2001; 158: 405–415.

    Article  CAS  PubMed  Google Scholar 

  65. Pizzagalli DA . Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology 2011; 36: 183–206.

    Article  PubMed  Google Scholar 

  66. Hunter AM, Korb AS, Cook IA, Leuchter AF . Rostral anterior cingulate activity in major depressive disorder: state or trait marker of responsiveness to medication?. J Neuropsychiatry Clin Neurosci 2013; 25: 126–133.

    Article  PubMed  Google Scholar 

  67. Fu CH, Steiner H, Costafreda SG . Predictive neural biomarkers of clinical response in depression: a meta-analysis of functional and structural neuroimaging studies of pharmacological and psychological therapies. Neurobiol Dis 2013; 52: 75–83.

    Article  CAS  PubMed  Google Scholar 

  68. Rentzsch J, Adli M, Wiethoff K, Gomez-Carrillo de Castro A, Gallinat J . Pretreatment anterior cingulate activity predicts antidepressant treatment response in major depressive episodes. Eur Arch Psychiatry Clin Neurosci 2013; 264: 213–223.

    Article  PubMed  Google Scholar 

  69. Milak MS, Parsey RV, Lee L, Oquendo MA, Olvet DM, Eipper F et al. Pretreatment regional brain glucose uptake in the midbrain on PET may predict remission from a major depressive episode after three months of treatment. Psychiatry Res 2009; 173: 63–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Nugent AC, Diazgranados N, Carlson PJ, Ibrahim L, Luckenbaugh DA, Brutsche N et al. Neural correlates of rapid antidepressant response to ketamine in bipolar disorder. Bipolar Disord 2013; 16: 119–128.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Wu JC, Gillin JC, Buchsbaum MS, Hershey T, Johnson JC, Bunney WE Jr . Effect of sleep deprivation on brain metabolism of depressed patients. Am J Psychiatry 1992; 149: 538–543.

    Article  CAS  PubMed  Google Scholar 

  72. McCormick LM, Boles Ponto LL, Pierson RK, Johnson HJ, Magnotta V, Brumm MC . Metabolic correlates of antidepressant and antipsychotic response in patients with psychotic depression undergoing electroconvulsive therapy. J ECT 2007; 23: 265–273.

    Article  CAS  PubMed  Google Scholar 

  73. McCormick LM, Yamada T, Yeh M, Brumm MC, Thatcher RW . Antipsychotic effect of electroconvulsive therapy is related to normalization of subgenual cingulate theta activity in psychotic depression. J Psychiatr Res 2009; 43: 553–560.

    Article  PubMed  Google Scholar 

  74. Langguth B, Wiegand R, Kharraz A, Landgrebe M, Marienhagen J, Frick U et al. Pre-treatment anterior cingulate activity as a predictor of antidepressant response to repetitive transcranial magnetic stimulation (rTMS). Neuro Endocrinol Lett 2007; 28: 633–638.

    PubMed  Google Scholar 

  75. Hernandez-Ribas R, Deus J, Pujol J, Segalas C, Vallejo J, Menchon JM et al. Identifying brain imaging correlates of clinical response to repetitive transcranial magnetic stimulation (rTMS) in major depression. Brain Stimulation 2013; 6: 54–61.

    Article  PubMed  Google Scholar 

  76. Broadway JM, Holtzheimer PE, Hilimire MR, Parks NA, Devylder JE, Mayberg HS et al. Frontal theta cordance predicts 6-month antidepressant response to subcallosal cingulate deep brain stimulation for treatment-resistant depression: a pilot study. Neuropsychopharmacology 2012; 37: 1764–1772.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Konarski JZ, Kennedy SH, Segal ZV, Lau MA, Bieling PJ, McIntyre RS et al. Predictors of nonresponse to cognitive behavioural therapy or venlafaxine using glucose metabolism in major depressive disorder. J Psychiatry Neurosci 2009; 34: 175–180.

    PubMed  PubMed Central  Google Scholar 

  78. Li JZ . Circadian rhythms and mood: opportunities for multi-level analyses in genomics and neuroscience. Bioessays 2014; 36: 305–315.

    Article  PubMed  Google Scholar 

  79. Jiang WG, Li SX, Zhou SJ, Sun Y, Shi J, Lu L . Chronic unpredictable stress induces a reversible change of PER2 rhythm in the suprachiasmatic nucleus. Brain Res 2011; 1399: 25–32.

    Article  CAS  PubMed  Google Scholar 

  80. Jiang WG, Li SX, Liu JF, Sun Y, Zhou SJ, Zhu WL et al. Hippocampal CLOCK protein participates in the persistence of depressive-like behavior induced by chronic unpredictable stress. Psychopharmacology (Berl) 2013; 227: 79–92.

    Article  CAS  Google Scholar 

  81. Kinoshita C, Miyazaki K, Ishida N . Chronic stress affects PERIOD2 expression through glycogen synthase kinase-3beta phosphorylation in the central clock. Neuroreport 2012; 23: 98–102.

    Article  CAS  PubMed  Google Scholar 

  82. Landgraf D, McCarthy MJ, Welsh DK . The role of the circadian clock in animal models of mood disorders. Behav Neurosci 2014; 128: 344–359.

    Article  PubMed  Google Scholar 

  83. Wongchitrat P, Mukda S, Phansuwan-Pujito P, Govitrapong P . Effect of amphetamine on the clock gene expression in rat striatum. Neurosci Lett 2013; 542: 126–130.

    Article  CAS  PubMed  Google Scholar 

  84. Masubuchi S, Honma S, Abe H, Nakamura W, Honma K . Circadian activity rhythm in methamphetamine-treated Clock mutant mice. Eur J Neurosci 2001; 14: 1177–1180.

    Article  CAS  PubMed  Google Scholar 

  85. Wu JC, Kelsoe JR, Schachat C, Bunney BG, DeModena A, Golshan S et al. Rapid and sustained antidepressant response with sleep deprivation and chronotherapy in bipolar disorder. Biol Psychiatry 2009; 66: 298–301.

    Article  CAS  PubMed  Google Scholar 

  86. Bunney BG, Bunney WE . Mechanisms of rapid antidepressant effects of sleep deprivation therapy: clock genes and circadian rhythms. Biol Psychiatry 2013; 73: 1164–1171.

    Article  CAS  PubMed  Google Scholar 

  87. Benedetti F, Colombo C . Sleep deprivation in mood disorders. Neuropsychobiology 2011; 64: 141–151.

    Article  PubMed  Google Scholar 

  88. Wirz-Justice A, Benedetti F., Terman M . Chronotherapeutics for Affective Disorders: A Clinician's Manual for Light and Wake Therapy. Karger: Basel, 2009.

    Book  Google Scholar 

  89. Wisor JP, O'Hara BF, Terao A, Selby CP, Kilduff TS, Sancar A et al. A role for cryptochromes in sleep regulation. BMC Neurosci 2002; 3: 20.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Wisor JP, Pasumarthi RK, Gerashchenko D, Thompson CL, Pathak S, Sancar A et al. Sleep deprivation effects on circadian clock gene expression in the cerebral cortex parallel electroencephalographic differences among mouse strains. J Neurosci 2008; 28: 7193–7201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Mongrain V, La Spada F, Curie T, Franken P . Sleep loss reduces the DNA-binding of BMAL1, CLOCK, and NPAS2 to specific clock genes in the mouse cerebral cortex. PLoS One 2011; 6: e26622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Thompson CL, Wisor JP, Lee CK, Pathak SD, Gerashchenko D, Smith KA et al. Molecular and anatomical signatures of sleep deprivation in the mouse brain. Front Neurosci 2010; 4: 165.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Maret S, Dorsaz S, Gurcel L, Pradervand S, Petit B, Pfister C et al. Homer1a is a core brain molecular correlate of sleep loss. Proc Natl Acad Sci USA 2007; 104: 20090–20095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Benedetti F, Dallaspezia S, Lorenzi C, Pirovano A, Radaelli D, Locatelli C et al. Gene-gene interaction of glycogen synthase kinase 3-beta and serotonin transporter on human antidepressant response to sleep deprivation. J Affect Disord 2012; 136: 514–519.

    Article  CAS  PubMed  Google Scholar 

  95. Benedetti F, Bernasconi A, Lorenzi C, Pontiggia A, Serretti A, Colombo C et al. A single nucleotide polymorphism in glycogen synthase kinase 3-beta promoter gene influences onset of illness in patients affected by bipolar disorder. Neurosci Lett 2004; 355: 37–40.

    Article  CAS  PubMed  Google Scholar 

  96. Benedetti F, Serretti A, Colombo C, Lorenzi C, Tubazio V, Smeraldi E . A glycogen synthase kinase 3-beta promoter gene single nucleotide polymorphism is associated with age at onset and response to total sleep deprivation in bipolar depression. Neurosci Lett 2004; 368: 123–126.

    Article  CAS  PubMed  Google Scholar 

  97. Beurel E, Song L, Jope RS . Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol Psychiatry 2011; 16: 1068–1070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Karege F, Perroud N, Burkhardt S, Fernandez R, Ballmann E, La Harpe R et al. Protein levels of beta-catenin and activation state of glycogen synthase kinase-3beta in major depression. A study with postmortem prefrontal cortex. J Affect Disord 2012; 136: 185–188.

    Article  CAS  PubMed  Google Scholar 

  99. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010; 329: 959–964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Cirelli C, Tononi G . Gene expression in the brain across the sleep-waking cycle. Brain Res 2000; 885: 303–321.

    Article  CAS  PubMed  Google Scholar 

  101. Mizoro Y, Yamaguchi Y, Kitazawa R, Yamada H, Matsuo M, Fustin JM et al. Activation of AMPA receptors in the suprachiasmatic nucleus phase-shifts the mouse circadian clock in vivo and in vitro. PLoS One 2010; 5: e10951.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Cirelli C, Tononi G . Differential expression of plasticity-related genes in waking and sleep and their regulation by the noradrenergic system. J Neurosci 2000; 20: 9187–9194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Chen C, Hardy M, Zhang J, LaHoste GJ, Bazan NG . Altered NMDA receptor trafficking contributes to sleep deprivation-induced hippocampal synaptic and cognitive impairments. Biochem Biophys Res Commun 2006; 340: 435–440.

    Article  CAS  PubMed  Google Scholar 

  104. Vecsey CG, Peixoto L, Choi JH, Wimmer M, Jaganath D, Hernandez PJ et al. Genomic analysis of sleep deprivation reveals translational regulation in the hippocampus. Physiol Genomics 2012; 44: 981–991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Cao R, Robinson B, Xu H, Gkogkas C, Khoutorsky A, Alain T et al. Translational control of entrainment and synchrony of the suprachiasmatic circadian clock by mTOR/4E-BP1 signaling. Neuron 2013; 79: 712–724.

    Article  CAS  PubMed  Google Scholar 

  106. Moller-Levet CS, Archer SN, Bucca G, Laing EE, Slak A, Kabiljo R et al. Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome. Proc Natl Acad Sci USA 2013; 110: E1132–E1141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Archer SN, Viola AU, Kyriakopoulou V, von Schantz M, Dijk DJ . Inter-individual differences in habitual sleep timing and entrained phase of endogenous circadian rhythms of BMAL1, PER2 and PER3 mRNA in human leukocytes. Sleep 2008; 31: 608–617.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Ackermann K, Plomp R, Lao O, Middleton B, Revell VL, Skene DJ et al. Effect of sleep deprivation on rhythms of clock gene expression and melatonin in humans. Chronobiol Int 2013; 30: 901–909.

    Article  CAS  PubMed  Google Scholar 

  109. Kavcic P, Rojc B, Dolenc-Groselj L, Claustrat B, Fujs K, Poljak M . The impact of sleep deprivation and nighttime light exposure on clock gene expression in humans. Croat Med J 2011; 52: 594–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Lavebratt C, Sjoholm LK, Soronen P, Paunio T, Vawter MP, Bunney WE et al. CRY2 is associated with depression. PLoS One 2010; 5: e9407.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Zarate C Jr., Machado-Vieira R, Henter I, Ibrahim L, Diazgranados N, Salvadore G . Glutamatergic modulators: the future of treating mood disorders?. Harv Rev Psychiatry 2010; 18: 293–303.

    Article  PubMed  PubMed Central  Google Scholar 

  112. DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry 2010; 71: 1605–1611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Larkin GL, Beautrais AL . A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. Int J Neuropsychopharmacol 2011; 14: 1127–1131.

    Article  CAS  PubMed  Google Scholar 

  114. Price RB, Nock MK, Charney DS, Mathew SJ . Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry 2009; 66: 522–526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Zigman D, Blier P . Urgent ketamine infusion rapidly eliminated suicidal ideation for a patient with major depressive disorder: a case report. J Clin Psychopharmacol 2013; 33: 270–272.

    Article  PubMed  Google Scholar 

  116. Zarate CA Jr., Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A et al. Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry 2012; 71: 939–946.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Harihar C, Dasari P, Srinivas JS . Intramuscular ketamine in acute depression: a report on two cases. Indian J Psychiatry 2013; 55: 186–188.

    Article  PubMed  PubMed Central  Google Scholar 

  118. De Gioannis A, De Leo D . Oral ketamine augmentation for chronic suicidality in treatment-resistant depression. Aust N Z J Psychiatry 2014; 48: 686.

    Article  PubMed  Google Scholar 

  119. Papolos DF, Teicher MH, Faedda GL, Murphy P, Mattis S . Clinical experience using intranasal ketamine in the treatment of pediatric bipolar disorder/fear of harm phenotype. J Affect Disord 2013; 147: 431–436.

    Article  CAS  PubMed  Google Scholar 

  120. Clements JA, Nimmo WS . Pharmacokinetics and analgesic effect of ketamine in man. Br J Anaesth 1981; 53: 27–30.

    Article  CAS  PubMed  Google Scholar 

  121. Browne CA, Lucki I . Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol 2013; 4: 161.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Kavalali ET, Monteggia LM . Synaptic mechanisms underlying rapid antidepressant action of ketamine. Am J Psychiatry 2012; 169: 1150–1156.

    Article  PubMed  Google Scholar 

  123. Bellet MM, Vawter MP, Bunney BG, Bunney WE, Sassone-Corsi P . Ketamine influences CLOCK:BMAL1 function leading to altered circadian gene expression. PLoS One 2011; 6: e23982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Maiese K, Chong ZZ, Shang YC, Wang S . mTOR: on target for novel therapeutic strategies in the nervous system. Trends Mol Med 2013; 19: 51–60.

    Article  CAS  PubMed  Google Scholar 

  125. Liu RJ, Fuchikami M, Dwyer JM, Lepack AE, Duman RS, Aghajanian GK . GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine. Neuropsychopharmacology 2013; 38: 2268–2277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Li SX, Liu LJ, Xu LZ, Gao L, Wang XF, Zhang JT et al. Diurnal alterations in circadian genes and peptides in major depressive disorder before and after escitalopram treatment. Psychoneuroendocrinology 2013; 38: 2789–2799.

    Article  CAS  PubMed  Google Scholar 

  127. Cuesta M, Clesse D, Pevet P, Challet E . New light on the serotonergic paradox in the rat circadian system. J Neurochem 2009; 110: 231–243.

    Article  CAS  PubMed  Google Scholar 

  128. Furey ML, Drevets WC . Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial. Arch Gen Psychiatry 2006; 63: 1121–1129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Monteggia LM, Kavalali ET . Scopolamine and ketamine: evidence of convergence?. Biol Psychiatry 2013; 74: 712–713.

    Article  CAS  PubMed  Google Scholar 

  130. Srinivasan V, Singh J, Pandi-Perumal SR, Brown GM, Spence DW, Cardinali DP . Jet lag, circadian rhythm sleep disturbances, and depression: the role of melatonin and its analogs. Adv Ther 2010; 27: 796–813.

    Article  CAS  PubMed  Google Scholar 

  131. Katz G, Knobler HY, Laibel Z, Strauss Z, Durst R . Time zone change and major psychiatric morbidity: the results of a 6-year study in Jerusalem. Compr Psychiatry 2002; 43: 37–40.

    Article  PubMed  Google Scholar 

  132. Chen Z, Yoo SH, Takahashi JS . Small molecule modifiers of circadian clocks. Cell Mol Life Sci 2012; 70: 2985–2998.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Pritzker Neuropsychiatric Disorders Research Fund, National Institute of Mental Health (NIMH) Conte Center Grant P50 MH60398, the William Lion Penzner Foundation (WEB), the Della Martin Foundation (WEB), NIMH R01MH085801 (MPV), R01MH104261 (HA and SJW), Office of Naval Research Grants ONR- N00014-12-1-0366 (HA and SJW) and the Hope for Depression Research Foundation, HDRF (HA and SJW). JZL is supported by a National Alliance for Research on Schizophrenia and Depression Abramson Family Foundation Investigator Award and an International Mental Health Research Organization–Johnson & Johnson Rising Star Translational Research Award.

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Bunney, B., Li, J., Walsh, D. et al. Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder. Mol Psychiatry 20, 48–55 (2015). https://doi.org/10.1038/mp.2014.138

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