Biological Rhythms Advance in Depressive Disorder

  • Wu Hong
  • Qinting ZhangEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1180)


Most processes of human body, such as brain function, are regulated by biological rhythms. Disturbance of biological rhythms impairs mood, behavior, cognition, sleep, and social activity and may lead to mental disorders. Disturbed rhythms are widely observable in patients with major depressive disorders (MDD) and make risk of onset, comorbidity, response of antidepressants, recurrence, cognition, social function, and complications of physical health. Therefore, it is crucial to assess and manage focus on biological rhythms for patients with MDD. There are several validated ways of assessing the biological rhythms, including 24 h fluctuations in cortisol or melatonin, sleep monitoring, actigraphy, and self-report scales. Chronotherapy, such as cognitive-behavioral therapy, interpersonal and social rhythm therapy, sleep deprivation, and bright light therapy was widely reported for treatment in patients with MDD. Monoamine antidepressants and lithium are attributed to regulation of biological rhythm. And some rhythm-regulated agents have been shown efficacy of antidepressant. Considering the crucial clinical significance of disturbed biological rhythms in MDD, we describe the mechanisms, clinical features, measurements, and treatments of the biological rhythms in patients with MDD.


Depressive disorder Biological rhythms Circadian Chronotherapy 


  1. Abe M, Herzog ED, Block GD (2000) Lithium lengthens the circadian period of individual suprachiasmatic nucleus neurons. NeuroReport 11(14):3261–3264CrossRefGoogle Scholar
  2. Albrecht U (2013) Circadian clocks and mood-related behaviors. Handb Exp Pharmacol 217:227–239. Scholar
  3. Avery DH, Shah SH, Eder DN et al (1999) Nocturnal sweating and temperature in depression. Acta Psychiatr Scand 100(4):295–301CrossRefGoogle Scholar
  4. Bahk YC, Han E, Lee SH (2014) Biological rhythm differences and suicidal ideation in patients with major depressive disorder. J Affect Disord 168:294–297. Scholar
  5. Bellivier F, Geoffroy PA, Etain B et al (2015) Sleep- and circadian rhythm-associated pathways as therapeutic targets in bipolar disorder. Expert Opin Ther Targets 19(6):747–763. Scholar
  6. Benca RM, Obermeyer WH, Thisted RA et al (1992) Sleep and psychiatric disorders: a meta-analysis. Arch Gen Psychiatry 49(8):651–668; discussion 669–670CrossRefGoogle Scholar
  7. Benedetti F, Barbini B, Campori E et al (2001) Sleep phase advance and lithium to sustain the antidepressant effect of total sleep deprivation in bipolar depression: new findings supporting the internal coincidence model? J Psychiatr Res 35(6):323–329CrossRefGoogle Scholar
  8. Benedetti F, Barbini B, Bernasconi A et al (2010) Acute antidepressant response to sleep deprivation combined with light therapy is influenced by the catechol-O-methyltransferase Val(108/158)Met polymorphism. J Affect Disord 121(1–2):68–72. Scholar
  9. Ben-Hamo M, Larson TA, Duge LS et al (2016) Circadian forced desynchrony of the master clock leads to phenotypic manifestation of depression in rats. eNeuro 3(6). Scholar
  10. Berdynaj D, Boudissa SN, Grieg MS et al (2016) Effect of chronotype on emotional processing and risk taking. Chronobiol Int 33(4):406–418. Scholar
  11. Bering T, Carstensen MB, Wörtwein G et al (2018) The circadian oscillator of the cerebral cortex: molecular, biochemical and behavioral effects of deleting the arntl clock gene in cortical neurons. Cereb Cortex 28(2):644–657. Scholar
  12. Bilello JA, Thurmond LM, Smith KM et al (2015) MDDScore: confirmation of a blood test to aid in the diagnosis of major depressive disorder. J Clin Psychiatry 76(2):e199–e206. Scholar
  13. Boland EM, Bertulis K, Leong SH et al (2019) Preliminary support for the role of reward relevant effort and chronotype in the depression/insomnia comorbidity. J Affect Disord 242:220–223. Scholar
  14. Bouwmans ME, Bos EH, Booij SH et al (2015) Intra- and inter-individual variability of longitudinal daytime melatonin secretion patterns in depressed and non-depressed individuals. Chronobiol Int 32(3):441–446. Scholar
  15. Brown GM, McIntyre RS, Rosenblat J et al (2018) Depressive disorders: processes leading to neurogeneration and potential novel treatments[J]. Prog Neuropsychopharmacol Biol Psychiatry 80(Pt C):189–204. Scholar
  16. Bumb JM, Enning F, Mueller JK et al (2016) Differential melatonin alterations in cerebrospinal fluid and serum of patients with major depressive disorder and bipolar disorder. Compr Psychiatry 68:34–39. Scholar
  17. Bunney BG, Bunney WE (2013) Mechanisms of rapid antidepressant effects of sleep deprivation therapy: clock genes and circadian rhythms. Biol Psychiatry 73(12):1164–1171. Scholar
  18. Buysse DJ, Frank E, Lowe KK et al (1997) Electroencephalographic sleep correlates of episode and vulnerability to recurrence in depression. Biol Psychiatry 41(4):406–418. Scholar
  19. Campbell SS, Gillin JC, Kripke DF et al (1989) Lithium delays circadian phase of temperature and REM sleep in a bipolar depressive: a case report. Psychiatry Res 27(1):23–29CrossRefGoogle Scholar
  20. Corruble E, Swartz HA, Bottai T et al (2016) Telephone-administered psychotherapy in combination with antidepressant medication for the acute treatment of major depressive disorder. J Affect Disord 190:6–11. Scholar
  21. Courtet P, Olié E (2012) Circadian dimension and severity of depression. Eur Neuropsychopharmacol 22(Suppl 3):S476–S481. Scholar
  22. Dallaspezia S, Benedetti F (2015a) Chronobiology of bipolar disorder: therapeutic implication. Curr Psychiatry Rep 17(8):606. Scholar
  23. Dallaspezia S, Benedetti F (2015b) Sleep deprivation therapy for depression. Curr Top Behav Neurosci 25:483–502. Scholar
  24. De Crescenzo F, Lennox A, Gibson JC et al (2017) Melatonin as a treatment for mood disorders: a systematic review. Acta Psychiatr Scand 136(6):549–558. Scholar
  25. Elder GJ, Wetherell MA, Barclay NL et al (2014) The cortisol awakening response–applications and implications for sleep medicine. Sleep Med Rev 18(3):215–224. Scholar
  26. Esaki Y, Kitajima T, Takeuchi I et al (2017) Effect of blue-blocking glasses in major depressive disorder with sleep onset insomnia: a randomized, double-blind, placebo-controlled study. Chronobiol Int 34(6):753–761. Scholar
  27. Fava M (2004) Daytime sleepiness and insomnia as correlates of depression. J Clin Psychiatry 65(Suppl 16):27–32PubMedGoogle Scholar
  28. Fava M, Targum SD, Nierenberg AA et al (2012) An exploratory study of combination buspirone and melatonin SR in major depressive disorder (MDD): a possible role for neurogenesis in drug discovery. J Psychiatr Res 46(12):1553–1563. Scholar
  29. Frank E, Swartz HA, Kupfer DJ (2000) Interpersonal and social rhythm therapy: managing the chaos of bipolar disorder. Biol Psychiatry 48(6):593–604CrossRefGoogle Scholar
  30. Germain A, Nofzinger EA, Meltzer CC et al (2007) Diurnal variation in regional brain glucose metabolism in depression. Biol Psychiatry 62(5):438–445. Scholar
  31. Giedke H, Schwärzler F (2002) Therapeutic use of sleep deprivation in depression. Sleep Med Rev 6(5):361–377CrossRefGoogle Scholar
  32. Goldstone A, Willoughby AR, de Zambotti M et al (2018) The mediating role of cortical thickness and gray matter volume on sleep slow-wave activity during adolescence. Brain Struct Funct 223(2):669–685. Scholar
  33. Hamers PC, Evenhuis HM, Hermans H (2017) A multicenter randomized controlled trial for bright light therapy in adults with intellectual disabilities and depression: study protocol and obstacle management. Res Dev Disabil 60:96–106. Scholar
  34. Havekes R, Meerlo P, Abel T (2015) Animal studies on the role of sleep in memory: from behavioral performance to molecular mechanisms. Curr Top Behav Neurosci 25:183–206. Scholar
  35. Haynes PL, Ancoli-Israel S, McQuaid J (2005) Illuminating the impact of habitual behaviors in depression. Chronobiol Int 22(2):279–297CrossRefGoogle Scholar
  36. Haynes PL, Gengler D, Kelly M (2016a) Social rhythm therapies for mood disorders: an update. Curr Psychiatry Rep 18(8):75. Scholar
  37. Haynes PL, Kelly M, Warner L et al (2016b) Cognitive behavioral social rhythm group therapy for veterans with posttraumatic stress disorder, depression, and sleep disturbance: results from an open trial. J Affect Disord 192:234–243. Scholar
  38. Hickie IB, Rogers NL (2011) Novel melatonin-based therapies: potential advances in the treatment of major depression. Lancet 378(9791):621–631. Scholar
  39. Hickie IB, Naismith SL, Robillard R et al (2013) Manipulating the sleep-wake cycle and circadian rhythms to improve clinical management of major depression. BMC Med 11:79. Scholar
  40. Hua P, Liu W, Chen D et al (2014) Cry1 and Tef gene polymorphisms are associated with major depressive disorder in the Chinese population. J Affect Disord 157:100–103. Scholar
  41. Huang KL, Lu WC, Wang YY et al (2014) Comparison of agomelatine and selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors in major depressive disorder: a meta-analysis of head-to-head randomized clinical trials. Aust NZ J Psychiatry 48(7):663–671. Scholar
  42. Jones SG, Benca RM (2015) Circadian disruption in psychiatric disorders. Sleep Med Clin 10(4):481–493. Scholar
  43. Joyce PR, Porter RJ, Mulder RT et al (2005) Reversed diurnal variation in depression: associations with a differential antidepressant response, tryptophan: large neutral amino acid ratio and serotonin transporter polymorphisms. Psychol Med 35(4):511–517CrossRefGoogle Scholar
  44. Kaladchibachi SA, Doble B, Anthopoulos N et al (2007) Glycogen synthase kinase 3, circadian rhythms, and bipolar disorder: a molecular link in the therapeutic action of lithium. J Circadian Rhythms 5:3. Scholar
  45. Kario K, Schwartz JE, Davidson KW et al (2001) Gender differences in associations of diurnal blood pressure variation, awake physical activity, and sleep quality with negative affect: the work site blood pressure study. Hypertension 38(5):997–1002CrossRefGoogle Scholar
  46. Kennedy SH, Avedisova A, Giménez-Montesinos N et al (2014) A placebo-controlled study of three agomelatine dose regimens (10 mg, 25 mg, 25–50 mg) in patients with major depressive disorder. Eur Neuropsychopharmacol 24(4):553–563. Scholar
  47. Ketchesin KD, Becker-Krail D, McClung CA (2018) Mood-related central and peripheral clocks. Eur J Neurosci.
  48. Khaleghipour S, Masjedi M, Ahade H et al (2012) Morning and nocturnal serum melatonin rhythm levels in patients with major depressive disorder: an analytical cross-sectional study. Sao Paulo Med J 130(3):167–172CrossRefGoogle Scholar
  49. Kragh M, Larsen ER, Martiny K et al (2018) Predictors of response to combined wake and light therapy in treatment-resistant inpatients with depression. Chronobiol Int 35(9):1209–1220. Scholar
  50. Lam RW (2006) Sleep disturbances and depression: a challenge for antidepressants. Int Clin Psychopharmacol 21(Suppl 1):S25–S29. Scholar
  51. Laux G, Barthel B, Hajak G et al (2017) Pooled analysis of four non-interventional studies: effectiveness and tolerability of the antidepressant agomelatine in daily practice. Adv Ther 34(4):895–914. Scholar
  52. Levitan RD (2007) The chronobiology and neurobiology of winter seasonal affective disorder. Dialogues Clin Neurosci 9(3):315–324PubMedPubMedCentralGoogle Scholar
  53. Li JZ, Bunney BG, Meng F et al (2013) Circadian patterns of gene expression in the human brain and disruption in major depressive disorder. Proc Natl Acad Sci USA 110(24):9950–9955. Scholar
  54. Lunsford-Avery JR, BDSB G, Brietzke E et al (2017) Adolescents at clinical-high risk for psychosis: circadian rhythm disturbances predict worsened prognosis at 1-year follow-up. Schizophr Res189:37–42. Scholar
  55. Ma HY, Liu ZF, Xu YF et al (2018) The association study of CLOCK gene polymorphisms with antidepressant effect in Chinese with major depressive disorder. Per Med. Scholar
  56. Marshall L, Helgadóttir H, Mölle M et al (2006) Boosting slow oscillations during sleep potentiates memory. Nature 444(7119):610–613. Scholar
  57. Martinotti G, Sepede G, Gambi F et al (2012) Agomelatine versus venlafaxine XR in the treatment of anhedonia in major depressive disorder: a pilot study. J Clin Psychopharmacol 32(4):487–491. Scholar
  58. McClung CA (2013) How might circadian rhythms control mood? Let me count the ways. Biol Psychiatry 74(4):242–249. Scholar
  59. Melo MCA, Abreu RLC, Linhares Neto VB et al (2017) Chronotype and circadian rhythm in bipolar disorder: a systematic review. Sleep Med Rev 34:46–58. Scholar
  60. Morris DW, Rush AJ, Jain S et al (2007) Diurnal mood variation in outpatients with major depressive disorder: implications for DSM-V from an analysis of the sequenced treatment alternatives to relieve depression study data. J Clin Psychiatry 68(9):1339–1347CrossRefGoogle Scholar
  61. Mukherjee S, Coque L, Cao JL et al (2010) Knockdown of clock in the ventral tegmental area through RNA interference results in a mixed state of mania and depression-like behavior. Biol Psychiatry 68(6):503–511. Scholar
  62. Naismith SL, Hermens DF, Ip TK et al (2012) Circadian profiles in young people during the early stages of affective disorder. Transl Psychiatry 2:e123. Scholar
  63. Nechita F, Pîrlog MC, ChiriŢă AL (2015) Circadian malfunctions in depression—neurobiological and psychosocial approaches. Rom J Morphol Embryol 56(3):949–955PubMedGoogle Scholar
  64. Nicolaides NC, Charmandari E, Chrousos GP et al (2014) Circadian endocrine rhythms: the hypothalamic-pituitary-adrenal axis and its actions. Ann NY Acad Sci 1318:71–80. Scholar
  65. Nussbaumer B, Kaminski-Hartenthaler A, Forneris CA et al (2015) Light therapy for preventing seasonal affective disorder. Cochrane Database Syst Rev (11):CD011269.
  66. Orozco-Solis R, Montellier E, Aguilar-Arnal L et al (2017) A circadian genomic signature common to ketamine and sleep deprivation in the anterior cingulate cortex. Biol Psychiatry 82(5):351–360. Scholar
  67. Quera-Salva MA, Lemoine P, Guilleminault C (2010) Impact of the novel antidepressant agomelatine on disturbed sleep-wake cycles in depressed patients. Hum Psychopharmacol 25(3):222–229. Scholar
  68. Rastad C, Wetterberg L, Martin C (2017) Patients’ experience of winter depression and light room treatment. Psychiatry J 2017:6867957. Scholar
  69. Robillard R, Hermens DF, Lee RS et al (2016) Sleep-wake profiles predict longitudinal changes in manic symptoms and memory in young people with mood disorders. J Sleep Res 25(5):549–555. Scholar
  70. Ronaldson A, Carvalho LA, Kostich K et al (2018) The effects of six-day SSRI administration on diurnal cortisol secretion in healthy volunteers. Psychopharmacology 235(12):3415–3422. Scholar
  71. Sachar EJ, Hellman L, Roffwarg HP et al (1973) Disrupted 24-hour patterns of cortisol secretion in psychotic depression. Arch Gen Psychiatry 28(1):19–24CrossRefGoogle Scholar
  72. Saini C, Morf J, Stratmann M et al (2012) Simulated body temperature rhythms reveal the phase-shifting behavior and plasticity of mammalian circadian oscillators. Genes Dev 26(6):567–580. Scholar
  73. Saus E, Soria V, Escaramís G et al (2010) Genetic variants and abnormal processing of pre-miR-182, a circadian clock modulator, in major depression patients with late insomnia. Hum Mol Genet 19(20):4017–4025. Scholar
  74. Schnell A, Albrecht U, Sandrelli F (2014) Rhythm and mood: relationships between the circadian clock and mood-related behavior. Behav Neurosci 128(3):326–343. Scholar
  75. Selemon LD, Zecevic N (2015) Schizophrenia: a tale of two critical periods for prefrontal cortical development. Transl Psychiatry 5:e623. Scholar
  76. Shi SQ, White MJ, Borsetti HM et al (2016) Molecular analyses of circadian gene variants reveal sex-dependent links between depression and clocks. Transl Psychiatry 6:e748. Scholar
  77. Soria V, Martínez-Amorós E, Escaramís G et al (2010) Differential association of circadian genes with mood disorders: CRY1 and NPAS2 are associated with unipolar major depression and CLOCK and VIP with bipolar disorder. Neuropsychopharmacology 35(6):1279–1289. Scholar
  78. Soterio-Pires JH, Hirotsu C, Kim LJ et al (2017) The interaction between erectile dysfunction complaints and depression in men: a cross-sectional study about sleep, hormones and quality of life. Int J Impot Res 29(2):70–75. Scholar
  79. Sprouse J, Braselton J, Reynolds L (2006) Fluoxetine modulates the circadian biological clock via phase advances of suprachiasmatic nucleus neuronal firing. Biol Psychiatry 60(8):896–899. Scholar
  80. Stahl SM, Fava M, Trivedi MH et al (2010) Agomelatine in the treatment of major depressive disorder: an 8-week, multicenter, randomized, placebo-controlled trial. J Clin Psychiatry 71(5):616–626. Scholar
  81. Takahashi JS, Hong HK, Ko CH et al (2008) The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat Rev Genet 9(10):764–775. Scholar
  82. Uz T, Ahmed R, Akhisaroglu M et al (2005) Effect of fluoxetine and cocaine on the expression of clock genes in the mouse hippocampus and striatum. Neuroscience 134(4):1309–1316. Scholar
  83. Yamaguchi N, Maeda K, Kuromaru S (1978) Sleep deprivation therapy for depression and diurnal rhythm of serum cortisol. Horumon to Rinsho 26(5):457–463PubMedGoogle Scholar
  84. Zajecka J, Schatzberg A, Stahl S et al (2010) Efficacy and safety of agomelatine in the treatment of major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled trial. J Clin Psychopharmacol 30(2):135–144. Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Division of Mood Disorders, Shanghai Mental Health CenterShanghai Jiao Tong University School of MedicineShanghaiChina
  2. 2.Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Academy of Forensic ScienceShanghaiChina

Personalised recommendations