Disruption of the circadian timing systems: molecular mechanisms in mood disorders.

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 MT(1), MT(2) receptor agonist and 5-HT(2c) 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.