Review: Clock genes at the heart of depression

The rhythms of life are ever pervasive, touching almost every aspect of our lives. We are finely tuned to the cycle of light and dark, so that we normally sleep during the night and are active during the day. Physiological rhythms are, however, not just slaves to the solar day, but are actually generated endogenously within the suprachiasmatic nuclei in the hypothalamus and are entrained via the retina. The circadian timing system is organized hierarchically with the suprachiasmatic nuclei providing neural and/or hormonal cues to the various organ systems, allowing them to express their own rhythmic physiological output. There is now a substantial body of evidence emerging that disruption of rhythmicity through altered sleep/wake patterns and exposure to light, or through endogenous disruption of key determinants of endogenous rhythms, can be detrimental to health. Circadian rhythm disturbances have long been associated with mood disorders, especially delayed sleep onset, and evidence is accumulating that alterations to the cellular timing system may underpin some aspects of the disorders. For example, mice carrying mutations in either Clock or per2 spend less time immobile in swim tests, which has been suggested as mimicking mania. In humans, single nucleotide polymorphisms in Clock and other clock genes have been associated with depression. With this increasing knowledge we may predict that new antidepressant drugs will emerge that, as a primary or secondary mechanism of action, target and correct abnormalities in the circadian timing system.