Enlightened: The connection between circadian rhythm and depression


  • Nancy Yang Simon Fraser University


All life on earth has evolved intricate clock systems to anticipate and adapt to the dynamic demands of a geophysical day. Rhythms can be found across the life kingdom and on several levels of organization – from genes to cells to organisms. Circadian rhythm is a tightly-regulated biological process that is both endogenously driven and entrained by environmental cues. Physiological processes, such as hormonal secretion, the stress system, and mood, follow observable circadian rhythms. The hypothalamic-pituitary-adrenal (HPA) axis is an important stress system in humans. Dysregulation in the HPA axis and circadian rhythms have been implicated in various metabolic diseases and depression.  This paper presents a critical review of the current literature on the relationship between the circadian regulation of the stress system and affective disorders.

Key words: circadian rhythms, depression, light, hypothalamic-pituitary-adrenal (HPA) axis, stress, corticotropin-releasing-hormone (CRH)



Mistlberger RE, Skene DJ. Nonphotic entrainment in humans?. Journal of biological rhythms. 2005 Aug 1;20(4):339-52.

Ishiura M, Kutsuna S, Aoki S, Iwasaki H, Andersson CR, Tanabe A, Golden SS, Johnson CH, Kondo T. Expression of a gene cluster kaiABC as a circadian feedback process in cyanobacteria. Science. 1998 Sep 4;281(5382):1519-23.

Baker CL, Loros JJ, Dunlap JC. The circadian clock of Neurospora crassa. FEMS microbiology reviews. 2012 Jan 1;36(1):95-110.

Wager-Smith K, Kay SA. Circadian rhythm genetics: from flies to mice to humans. Nature genetics. 2000 Sep 1;26(1):23-7.

Pittendrigh C.S. Temporal organization: reflections of a Darwinian clock-watcher. Annu. Rev. Physiol., 55 (1993), pp. 16–54

Hastings, M.H. Central clocking. Trends Neurosci., 20 (1997), pp.459-464

Kelin, D.C.., Moore, R.Y., Reppert, S.M. Suprachiasmatic Nucleus:The Mind's Clock. Oxford University Press, New York: NY (1991)

Welsh, D.K., Logothetis, D.K, Meister, M., Reppert, S.M., Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms. Neuron, 14 (1995), pp. 697–706

Monteleone, P., Maj, M. The circadian basis of mood disorders: recent development and treatment implications. European Neuropsychopharmacology. 2008; 18 (10):701-711. http://dx.doi.org/10.1016/j.euroneuro.2008.06.007

MooreR.Y., Speh J.C.. Serotonin innervation of the primate suprachiasmatic nucleus. Brain Res., 1010 (2004), pp. 169–173

Wirz-Justice, A. Biological rhythm disturbances in mood disorder. Int. Clin. Psychopharmacol. (Suppl. 1) (2006), pp. S11–S15

Yesavage J, Noda A, Hernandez B, Friedman L, Cheng J, Tinklenberg J et al. Circadian Clock Gene Polymorphisms and Sleep–Wake Disturbance in Alzheimer Disease. The American Journal of Geriatric Psychiatry. 2011;19(7):635-643.

Spiegel K, Knutson K, Leproult R, Tasali E, Van Cauter E. Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes. Journal of applied physiology. 2005 Nov 1;99(5):2008-19.

Savvidis C, Koutsilieris M. Circadian rhythm disruption in cancer biology. Mol Med. 2012 Dec 6;18(1):1249-60.

Kalsbeek A, Van der Spek R, Lei J, Endert E, Buijs RM, Fliers E. Circadian rhythms in the hypothalamus–pituitary–adrenal (HPA) axis. Molecular and cellular endocrinology. 2012 Feb 5;349(1):20-9.

Tsigos C, Chrousos GP. Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress. Journal of psychosomatic research. 2002 Oct 31;53(4):865-71.

Mohawk JA, Green CB, Takahashi JS. Central and peripheral circadian clocks in mammals. Annual review of neuroscience. 2012 Jul 21;35:445-62.

Miller GE, Chen E, Zhou ES. If it goes up, must it come down? Chronic stress and the hypothalamic-pituitary-adrenocortical axis in humans. Psychological bulletin. 2007 Jan;133(1):25.

Claes SJ. CRH, stress, and major depression: a psychobiological interplay. Vitamins & Hormones. 2004 Dec 31;69:117-50.

Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends in neurosciences. 2008 Sep 30;31 (9):464-8.

Wong ML, Kling MA, Munson PJ, Listwak S, Licinio J, Prolo P, Karp B, McCutcheon IE, Geracioti TD, DeBellis MD, Rice KC. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone. Proceedings of the National Academy of Sciences. 2000 Jan 4;97(1):325-30.

Germain A, Kupfer DJ. Circadian rhythm disturbances in depression. Human Psychopharmacology: Clinical and Experimental. 2008 Oct 1;23(7):571-85

Gold P.W., Chrousos G.P., Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Molecular psychiatry. 2002 Jan 1;7(3):254.

Butler PW, Besser GM. Pituitary-adrenal function in severe depressive illness. The Lancet. 1968 Jun 8;291(7554):1234-6.

Nemeroff CB, Krishnan KR, Reed D, Leder R, Beam C, Dunnick NR. Adrenal gland enlargement in major depression: a computed tomographic study. Archives of general psychiatry. 1992 May 1;49(5):384-388.

Geracioti TD, Loosen PT, Orth DN. Low cerebrospinal fluid corticotropin-releasing hormone concentrations in eucortisolemic depression. Biological psychiatry. 1997 Aug 1;42(3):165-74.

Anisman H, Ravindran A, Griffiths J, Merali Z. Endocrine and cytokine correlates of major depression and dysthymia with typical or atypical. Molecular psychiatry. 1999;4:182-8.

Scheer FA, Buijs RM. Light affects morning salivary cortisol in humans. Journal of Clinical Endocrinology and Metabolism. 1999 Sep 1;84:3395-8.

Koenigsberg HW, Teicher MH, Mitropoulou V, Navalta C, New AS, Trestman R, Siever LJ. 24-h Monitoring of plasma norepinephrine, MHPG, cortisol, growth hormone and prolactin in depression. Journal of psychiatric research. 2004 Oct 31;38(5):503-11.

Dahl RE, Ryan ND, Puig-Antich J, Nguyen NA, Al-Shabbout M, Meyer VA, Perel J. 24-hour cortisol measures in adolescents with major depression: a controlled study. Biological Psychiatry. 1991 Jul 1;30(1):25-36.

Martiny K, Lunde M, Unden M, Dam H, Bech P. Adjunctive bright light in non‐seasonal major depression: results from clinician‐rated depression scales. Acta Psychiatrica Scandinavica. 2005 Aug 1;112(2):117-25.

Lewy AJ, Cutler NL, Sack RL. The endogenous melatonin profile as a marker for circadian phase position. Journal of biological rhythms. 1999 Jun;14(3):227-36.

Almeida OP, Pfaff JJ. Sleep complaints among older general practice patients: association with depression. Br J Gen Pract. 2005 Nov 1;55(520):864-6.

Claustrat B, Chazot G, Brun J, Jordan D, Sassolas G. A chronobiological study of melatonin and cortisol secretion in depressed subjects: plasma melatonin, a biochemical marker in major depression. Biol Psychiatry. 1984 Aug;19(8):1215-28.

Avery DH, Wildschiødtz G, Rafaelsen OJ. Nocturnal temperature in affective disorder. Journal of affective disorders. 1982 Mar 31;4(1):61-71.

Goodwin FK, Jamison KR. Manic-depressive illness: bipolar disorders and recurrent depression. Oxford University Press; 2007 Mar 22.

Sohn CH, Lam RW. Treatment of seasonal affective disorder: unipolar versus bipolar differences. Current psychiatry reports. 2004 Dec 1;6(6):478-85.

Ryves WJ, Harwood AJ. Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. Biochemical and biophysical research communications. 2001 Jan 26;280(3):720-5.

LeSauter J, Silver R. Lithium lengthens the period of circadian rhythms in lesioned hamsters bearing SCN grafts. Biological psychiatry. 1993 Jul 15;34(1):75-83.

Ogden CA, Rich ME, Schork NJ, Paulus MP, Geyer MA, Lohr JB, Kuczenski R, Niculescu AB. Candidate genes, pathways and mechanisms for bipolar (manic–depressive) and related disorders: an expanded convergent functional genomics approach. Molecular psychiatry. 2004 Nov 1;9(11):1007-29.

Sumaya IC, Rienzi BM, Deegan JF, Moss DE. Bright light treatment decreases depression in institutionalized older adults a placebo-controlled crossover study. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2001 Jun


Phelps J. Dark therapy for bipolar disorder using amber lenses for blue light blockade. Medical hypotheses. 2008 Dec 31;70(2):224-9.