From circadian rhythms to clock genes in depression.

Depression, particularly unipolar depression, has often been linked to circadian (i.e. approximately 24-h) rhythm abnormalities. The observation that many diverse rhythms are disrupted in depressed patients indicates that such disturbances are not unique to specific rhythms, but instead are of a more central origin (i.e. involve the central circadian pacemaker and/or the molecular circadian clock core machinery). One rhythm that is often disrupted in depression is the sleep-wake cycle - a disruption that, in turn, might lead to other rhythm disturbances. Thus, there are two general ways in which disrupted circadian rhythms could lead to depression: (i) disorganization within the circadian system could itself lead to neurobiological dysfunction and (ii) a circadian disturbance of the normal sleep-wake cycle could facilitate or exacerbate the depressed state. The recent discovery of the molecular clock responsible for the generation of circadian rhythms provides novel mechanistic insights into how rhythm abnormalities might lead to disrupted behavioural states, and offers new therapeutic avenues for the treatment of the timing abnormalities that might underlie depression. The finding that the molecular circadian clock is present in many cells in the central nervous system and regulates the timing of the expression of at least 10% of the transcripts in many tissues emphasizes how circadian dysfunction could have drastic consequences for normal physiological function in the brain.