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.