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.

Clinical signs of circadian dysregulation in depression

The clinical finding that depression-related symptoms include sleep-wake disorder with nocturnal insomnia and daytime sleepiness, lack of activity, loss of appetite, and diurnal changes of mood has encouraged the idea that abnormalities in circadian rhythms may underlie the development of affective disorders. From the point of view of clinical psychiatrists, quite a number of depressive symptoms have a temporal pattern that parallels the circadian malfunction found in the biological parameters. Beside symptoms of a disturbed sleep-wake cycle, diurnal variation in depressive symptoms appears to be central to the core of depression. Yet, longitudinal investigation of individual temporal pattern, regularity, and relation to clinical state and clinical improvement has revealed little homogeneity. Morning lows, afternoon slump, evening worsening can all occur during a single depressive episode. Mood variability, or the propensity to produce mood swings, appears to be the characteristic that most predicts the capacity to respond to treatment.

Circadian functions as targets in the treatment of mood disorders

The corresponding clinical and neurobiological findings in depression have stimulated the idea that the restoration of normal circadian rhythms could have antidepressant potential. It is well established that chronotherapeutics- behavioral and biological treatments based on the principle of circadian rhythm reorganization - contribute significantly to the treatment of affective disorders. These clinical interventions include sleep deprivation, shifting of sleep time (sleep phase advance), light and dark therapy, as well as circadian behavioral entrainment strategies (eg, social rhythm therapy). In contrast to pharmacological treatments, some chronobiological interventions such as sleep deprivation treatment dramatically reduce depressive symptoms within 24-48 hours in 40%-60% of depressed subjects. The aim of chronotherapeutic interventions, thought to act by shifting and resetting the circadian clock, is to normalize circadian disturbances in depression. A growing number of clinical studies support the usefulness of chronotherapeutic interventions, even as first-line treatment. Consensus has not yet been achieved in terms of defining the underlying chronobiological mechanisms of optimal methods of producing rapid and sustained antidepressant responses to circadian interventions. The therapeutic effects of such interventions are rapid and often transient, but they can be stabilized by combining them with other such interventions, or by combining them with common drug treatments or biophysical treatments like repetitive transcranial magnetic stimulation.