Abstract
Depression is one of the leading causes of morbidity worldwide and represents a huge burden to society. As with many other psychiatric disorders, a genetic basis for depression has been identified. Evidence for the role of circadian genes in depression is particularly compelling. Circadian gene mutations are also associated with circadian rhythm disorders such as familial advanced sleep phase syndrome, delayed sleep phase syndrome, and non-24-hour sleep-wake syndrome. Such disorders, plus the other manifestations of a disrupted circadian system such as hormone dysregulation, are often observed among those with depression. This suggests a shared aetiology between circadian disruption and depression, although the exact mechanisms underlying the association are unclear. This paper reviews the molecular mechanisms involved in depression, with an emphasis on circadian genes.
Twin studies in depression have reported probandwise concordance rates of 40% and 70% using narrow and broad diagnostic criteria, respectively, and heritability of over 85% for bipolar disorder. In association studies, increased susceptibility to depression has been noted in those with polymorphisms in the following: D-amino-acid-oxidase activator/G30 gene complex, glucocorticoid receptor gene, serotonin transporter gene, tryptophan hydroxylase 2 gene, dopamine transporter gene and G protein-coupled receptor 50 gene. Polymorphisms in these genes have also been linked to a better or worse response to antidepressant therapy, an increased likelihood of responding poorly to adversity and increased suicide ideation.
Polymorphisms in the CLOCK, BMAL1, Per3 and TIMELESS genes have been associated with susceptibility to mood disorder, and single nucleotide polymorphisms and haplotypes in several circadian genes have been observed among those displaying certain circadian phenotypes, including worse mood in the evening, insomnia in mania and early, middle or late insomnia in depression.
Manipulation of the circadian timing system via sleep deprivation, bright light or pharmacological therapy has also been shown to alleviate depressive symptoms, providing further evidence for the role of circadian dysfunction in depression pathophysiology. The new antidepressant agomelatine is the first melatonergic antidepressant with an innovative mode of action: it is a melatonergic MT1, MT2 receptor agonist and 5-HT2C antagonist, and is able to restore the internal clock, which is profoundly disturbed in depression, thus being efficacious in major depressive disorders.
In conclusion, a wealth of evidence is now available supporting a genetic basis for depression. The apparent importance of mutations in the circadian genes in determining disease susceptibility, disease recurrence and response to treatment suggests that the circadian pathway represents an attractive target for pharmacological manipulation to improve management of this debilitating disorder.
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References
Kent L, Doerry U, Hardy E, et al. Evidence that variation at the serotonin transporter gene influences susceptibility to attention deficit hyperactivity disorder (ADHD): analysis and pooled analysis. Mol Psychiatry 2002; 7(8): 908–12
Chumakov I, Blumenfeld M, Guerassimenko O, et al. Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci U S A 2002 Oct 15; 99(21): 13675–80
Isbir T, Agachan B, Yilmaz H, et al. Interaction between apolipoprotein-E and angiotensin-converting enzyme genotype in Alzheimer’s disease. Am J Alzheimers Dis Other Demen 2001 Jul–Aug; 16(4): 205–10
Hammoumi S, Payen A, Favre JD, et al. Does the short variant of the serotonin transporter linked polymorphic region constitute a marker of alcohol dependence? Alcohol 1999 Feb; 17(2): 107–12
Ustun TB, Ayuso-Mateos JL, Chatterji S, et al. Global burden of depressive disorders in the year 2000. Br J Psychiatry 2004 May; 184: 386–92
Bostwick JM, Pankratz VS. Affective disorders and suicide risk: a reexamination. Am J Psychiatry 2000 Dec; 157(12): 1925–32
Tylee A, Gastpar M, Lepine JP, et al. DEPRES II (Depression Research in European Society II): a patient survey of the symptoms, disability and current management of depression in the community. DEPRES Steering Committee. Int Clin Psychopharmacol 1999 May; 14(3): 139–51
Bertelsen A, Harvald B, Hauge M. A Danish twin study of manic-depressive disorders. Br J Psychiatry 1977 Apr; 130: 330–51
McGuffin P, Rijsdijk F, Andrew M, et al. The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry 2003 May; 60(5): 497–502
Kieseppa T, Partonen T, Haukka J, et al. High concordance of bipolar I disorder in a nationwide sample of twins. Am J Psychiatry 2004 Oct; 161(10): 1814–21
Cardno AG, Marshall EJ, Coid B, et al. Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen Psychiatry 1999 Feb; 56(2): 162–8
McGuffin P, Katz R, Watkins S, et al. A hospital-based twin register of the heritability of DSM-IV unipolar depression. Arch Gen Psychiatry 1996 Feb; 53(2): 129–36
Mendlewicz J. The search for a manic depressive gene: from classical to molecular genetics. Prog Brain Res 1994; 100: 255–9
Chen YS, Akula N, Detera-Wadleigh SD, et al. Findings in an independent sample support an association between bipolar affective disorder and the G72/G30 locus on chromosome 13q33. Mol Psychiatry 2004 Jan; 9(1): 87–92; image 5
Hattori E, Liu C, Badner JA, et al. Polymorphisms at the G72/G30 gene locus, on 13q33, are associated with bipolar disorder in two independent pedigree series. Am J Hum Genet 2003 May; 72(5): 1131–40
Schumacher J, Jamra RA, Freudenberg J, et al. Examination of G72 and D-amino-acid oxidase as genetic risk factors for schizophrenia and bipolar affective disorder. Mol Psychiatry 2004 Feb; 9(2): 203–7
Williams NM, Green EK, Macgregor S, et al. Variation at the DAOA/G30 locus influences susceptibility to major mood episodes but not psychosis in schizophrenia and bipolar disorder. Arch Gen Psychiatry 2006 Apr; 63(4): 366–73
Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 2000 Nov; 23(5): 477–501
van Rossum EF, Binder EB, Majer M, et al. Polymorphisms of the glucocorticoid receptor gene and major depression. Biol Psychiatry 2006 Apr 15; 59(8): 681–8
Bet PM, Penninx BW, Bochdanovits Z, et al. Glucocorticoid receptor gene polymorphisms and childhood adversity are associated with depression: New evidence for a gene-environment interaction. Am J Med Genet B Neuropsychiatr Genet 2009 Jul 5; 150B(5): 660–9
Lucki I. The spectrum of behaviors influenced by serotonin. Biol Psychiatry 1998 Aug 1; 44(3): 151–62
Elhwuegi AS. Central monoamines and their role in major depression. Prog Neuropsychopharmacol Biol Psychiatry 2004 May; 28(3): 435–51
Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003 Jul 18; 301(5631): 386–9
Grunblatt E, Loffler C, Zehetmayer S, et al. Association study of the 5-HTTLPR polymorphism and depression in 75-year-old nondemented subjects from the Vienna Transdanube Aging (VITA) study. J Clin Psychiatry 2006 Sep; 67(9): 1373–8
De Luca V, Likhodi O, Van Tol HH, et al. Gene expression of tryptophan hydroxylase 2 in post-mortem brain of suicide subjects. Int J Neuropsychopharmacol 2006 Feb; 9(1): 21–5
Harvey M, Gagne B, Labbe M, et al. Polymorphisms in the neuronal isoform of tryptophan hydroxylase 2 are associated with bipolar disorder in French Canadian pedigrees. Psychiatr Genet 2007 Feb; 17(1): 17–22
Lopez VA, Detera-Wadleigh S, Cardona I, et al. Nested association between genetic variation in tryptophan hydroxylase II, bipolar affective disorder, and suicide attempts. Biol Psychiatry 2007 Jan 15; 61(2): 181–6
Thomson PA, Wray NR, Thomson AM, et al. Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor. Mol Psychiatry 2005 May; 10(5): 470–8
Mendlewicz J, Sevy S, Mendelbaum K. Minireview: Molecular genetics in affective illness. Life Sci 1993; 52(3): 231–42
Haeffel GJ, Getchell M, Koposov RA, et al. Association between polymorphisms in the dopamine transporter gene and depression: evidence for a gene-environment interaction in a sample of juvenile detainees. Psychol Sci 2008 Jan; 19(1): 62–9
Kato M, Fukuda T, Serretti A, et al. ABCB1 (MDR1) gene polymorphisms are associated with the clinical response to paroxetine in patients with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2008 Feb 15; 32(2): 398–404
Moore RY. Organization and function of a central nervous system circadian oscillator: the suprachiasmatic hypothalamic nucleus. Fed Proc 1983 Aug; 42(11): 2783–9
Barnard AR, Nolan PM. When clocks go bad: neurobehavioural consequences of disrupted circadian timing. PLoS Genet 2008 May; 4(5): e1000040
Cermakian N, Boivin DB. A molecular perspective of human circadian rhythm disorders. Brain Res Brain Res Rev 2003 Jun; 42(3): 204–20
Harms E, Kivimae S, Young MW, et al. Posttranscriptional and posttranslational regulation of clock genes. J Biol Rhythms 2004 Oct; 19(5): 361–73
McClung CA. Circadian genes, rhythms and the biology of mood disorders. Pharmacol Ther 2007 May; 114(2): 222–32
Reppert SM, Weaver DR. Coordination of circadian timing in mammals. Nature 2002 Aug 29; 418(6901): 935–41
Lamont EW, Diaz LR, Barry-Shaw J, et al. Daily restricted feeding rescues a rhythm of period2 expression in the arrhythmic suprachiasmatic nucleus. Neuroscience 2005; 132(2): 245–8
Tataroglu O, Davidson AJ, Benvenuto LJ, et al. The methamphetamine-sensitive circadian oscillator (MASCO) in mice. J Biol Rhythms 2006 Jun; 21(3): 185–94
Akashi M, Tsuchiya Y, Yoshino T, et al. Control of intracellular dynamics of mammalian period proteins by casein kinase I epsilon (CKIepsilon) and CKIdelta in cultured cells. Mol Cell Biol 2002 Mar; 22(6): 1693–703
Xu Y, Padiath QS, Shapiro RE, et al. Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature 2005 Mar 31; 434(7033): 640–4
Toh KL, Jones CR, He Y, et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 2001 Feb 9; 291(5506): 1040–3
Xu Y, Toh KL, Jones CR, et al. Modeling of a human circadian mutation yields insights into clock regulation by PER2. Cell 2007 Jan 12; 128(1): 59–70
Carpen JD, von Schantz M, Smits M, et al. A silent polymorphism in the PER1 gene associates with extreme diurnal preference in humans. J Hum Genet 2006; 51(12): 1122–5
Ebisawa T, Uchiyama M, Kajimura N, et al. Association of structural polymorphisms in the human period3 gene with delayed sleep phase syndrome. EMBO Rep 2001 Apr; 2(4): 342–6
Archer SN, Robilliard DL, Skene DJ, et al. A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference. Sleep 2003 Jun 15; 26(4): 413–5
Iwase T, Kajimura N, Uchiyama M, et al. Mutation screening of the human Clock gene in circadian rhythm sleep disorders. Psychiatry Res 2002 Mar 15; 109(2): 121–8
Takano A, Uchiyama M, Kajimura N, et al. A missense variation in human casein kinase I epsilon gene that induces functional alteration and shows an inverse association with circadian rhythm sleep disorders. Neuropsychopharmacology 2004 Oct; 29(10): 1901–9
Campbell SS, Murphy PJ, van den Heuvel CJ, et al. Etiology and treatment of intrinsic circadian rhythm sleep disorders. Sleep Med Rev 1999 Sep; 3(3): 179–200
Benedetti F, Serretti A, Colombo C, et al. Influence of CLOCK gene polymorphism on circadian mood fluctuation and illness recurrence in bipolar depression. Am J Med Genet B Neuropsychiatr Genet 2003 Nov 15; 123B(1): 23–6
Shi J, Wittke-Thompson JK, Badner JA, et al. Clock genes may influence bipolar disorder susceptibility and dysfunctional circadian rhythm. Am J Med Genet B Neuropsychiatr Genet 2008 Oct 5; 147B(7): 1047–55
Mansour HA, Wood J, Logue T, et al. Association study of eight circadian genes with bipolar I disorder, schizoaffective disorder and schizophrenia. Genes Brain Behav 2006 Mar; 5(2): 150–7
Nievergelt CM, Kripke DF, Barrett TB, et al. Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 2006 Apr 5; 141B(3): 234–41
Artioli P, Lorenzi C, Pirovano A, et al. How do genes exert their role? Period3 gene variants and possible influences on mood disorder phenotypes. Eur Neuropsychopharmacol 2007 Sep; 17(9): 587–94
Benedetti F, Serretti A, Colombo C, et al. 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 Sep 23; 368(2): 123–6
Desan PH, Oren DA, Malison R, et al. Genetic polymorphism at the CLOCK gene locus and major depression. Am J Med Genet 2000 Jun 12; 96(3): 418–21
Lee KY, Ahn YM, Joo EJ, et al. No association of two common SNPs at position −1727 A/T, −50 C/T of GSK-3 beta polymorphisms with schizophrenia and bipolar disorder of Korean population. Neurosci Lett 2006 Mar 6; 395(2): 175–8
Szczepankiewicz A, Rybakowski JK, Suwalska A, et al. Association study of the glycogen synthase kinase-3beta gene polymorphism with prophylactic lithium response in bipolar patients. World J Biol Psychiatry 2006; 7(3): 158–61
Mendlewicz J, Linkowski P. Hypothalamic functions, sleep and circadian rhythms in affective disorders. Adv Biochem Psychopharmacol 1987; 43: 221–36
Shirayama M, Shirayama Y, Iida H, et al. The psychological aspects of patients with delayed sleep phase syndrome (DSPS). Sleep Med 2003 Sep; 4(5): 427–33
Hamet P, Tremblay J. Genetics of the sleep-wake cycle and its disorders. Metabolism 2006 Oct; 55(10 Suppl 2): S7–12
Ehlers CL, Frank E, Kupfer DJ. Social zeitgebers and biological rhythms. A unified approach to understanding the etiology of depression. Arch Gen Psychiatry 1988 Oct; 45(10): 948–52
Keller J, Flores B, Gomez RG, et al. Cortisol circadian rhythm alterations in psychotic major depression. Biol Psychiatry 2006 Aug 1; 60(3): 275–81
Owens MJ, Nemeroff CB. Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 1994 Feb; 40(2): 288–95
Lewy AJ, Lefler BJ, Emens JS, et al. The circadian basis of winter depression. Proc Natl Acad Sci U S A 2006 May 9; 103(19): 7414–9
Mendlewicz J, Branchey L, Weinberg U, et al. The 24 hour pattern of plasma melatonin in depressed patients before and after treatment. Commun Psychopharmacol 1980; 4(1): 49–55
Mendlewicz J, Linkowski P, Branchey L, et al. Abnormal 24 hour pattern of melatonin secretion in depression. Lancet 1979 Dec 22–29; 2(8156–8157): 1362
Rusting CL, Larsen RJ. Diurnal patterns of unpleasant mood: associations with neuroticism, depression, and anxiety. J Pers 1998 Feb; 66(1): 85–103
Wirz-Justice A, Van den Hoofdakker RH. Sleep deprivation in depression: what do we know, where do we go? Biol Psychiatry. 1999 Aug 15; 46(4): 445–53
Terman M, Terman JS. Light therapy for seasonal and nonseasonal depression: efficacy, protocol, safety, and side effects. CNS Spectr 2005 Aug; 10(8): 647–63; quiz 72
Klemfuss H. Rhythms and the pharmacology of lithium. Pharmacol Ther 1992; 56(1): 53–78
Sprouse J, Braselton J, Reynolds L. Fluoxetine modulates the circadian biological clock via phase advances of suprachiasmatic nucleus neuronal firing. Biol Psychiatry 2006 Oct 15; 60(8): 896–9
Loo H, Hale A, D’Haenen H. Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT(2C) antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study. Int Clin Psychopharmacol 2002 Sep; 17(5): 239–47
Olie JP, Kasper S. Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder. Int J Neuropsychopharmacol 2007 Oct; 10(5): 661–73
Leproult R, Van Onderbergen A, L’Hermite-Baleriaux M, et al. Phase-shifts of 24-h rhythms of hormonal release and body temperature following early evening administration of the melatonin agonist agomelatine in healthy older men. Clin Endocrinol (Oxf) 2005 Sep; 63(3): 298–304
Lemoine P, Guilleminault C, Alvarez E. Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine: randomized, double-blind comparison with venlafaxine. J Clin Psychiatry 2007 Nov; 68(11): 1723–32
Audinot V, Mailliet F, Lahaye-Brasseur C, et al. New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn Schmiedebergs Arch Pharmacol 2003 Jun; 367(6): 553–61
Popoli M. Circadian rhythms: Strong evidence on how to treat the core of depression. CNS Drugs 2009; 23Suppl. 2: 27–34
Acknowledgements
Medical writing support was provided by Claire Byrne from Wolters Kluwer Health and was funded by Servier.
The author is a member of the Advisory Board of Servier and of the board of the Lundbeck Neuroscience Institute.
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Mendlewicz, J. Disruption of the Circadian Timing Systems. CNS Drugs 23 (Suppl 2), 15–26 (2009). https://doi.org/10.2165/11318630-000000000-00000
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DOI: https://doi.org/10.2165/11318630-000000000-00000