An MJA editorial on circadian rhythms published nearly 40 years ago lamented the “neglect ... in part engendered by the air of mysticism which surrounded much of the earlier work in this field” that had obscured recognition of their importance to health.1 Since that time, basic research has explored various aspects, including the intracellular generation of circadian oscillations, their intercellular synchronisation, the entrainment of the circadian “system” by environmental time cues or “zeitgebers” such as light, and circadian variation in biological functioning. Further, clinical research has focused on the consequences of circadian disruption, circadian rhythm sleep disorders (CRSDs), circadian abnormalities in affective disorders, and chronotherapy. Here, we summarise some of these key advances.

In 1970, it was known that circadian rhythms are generated endogenously,1 but little was known about the mechanisms involved. The discovery of the first circadian clock gene, in the fruit fly Drosophila melanogaster, was reported the following year.2 A number of mammalian clock genes have now been identified, and there is considerable understanding of the transcription–translation feedback loops that generate circadian oscillations at the cellular level.3 In 1972, the importance to circadian pacing of the suprachiasmatic nuclei (SCN) in the anterior hypothalamus was established. The SCN comprise the “master” circadian clock, which plays a key role in synchronising peripheral (“slave”) oscillators and in the entrainment of the circadian system by light.3 Light information from melanopsin-containing retinal ganglion cells is transferred directly to the SCN via the retino-hypothalamic tract and indirectly via the retino-geniculo-hypothalamic tract. The SCN interpret and transfer this information to the pineal gland, which secretes melatonin accordingly. In the future, further understanding of normal circadian regulation will help to clarify abnormalities that occur in circadian disruption and disorders and hopefully indicate effective strategies for circadian “resetting”.

In industrialised societies, 15%–20% of workers are involved in shift work or unusual work hours, and it has been reported that prolonged circadian disruption, especially from rotating night-shift work, increases the risk of cardiovascular disease,4 metabolic syndrome,5 and prostate, breast and colorectal cancer.6 Although important, questions remain about the evidence and explanation for these findings. For example, a recent systematic review concluded that there is limited evidence for the suggested link with breast cancer and insufficient evidence for a causal link with cancer overall.7 There is experimental evidence that circadian disruption can independently produce adverse metabolic and cardiovascular effects,8 but uncertainty remains about the extent to which other factors associated with shift work, particularly sleep disturbance,9 have contributed to reported findings from clinical studies. It is recognised that shift workers are more liable to injuries at work and road accidents when driving home from work, but circadian disruption is probably not solely responsible for this. Despite the need for further clarification, there appears to be sufficient evidence of the ill effects associated with rotating shift work to justify simple precautionary measures: identifying, educating and monitoring shift workers; improving rosters by including shorter shifts; avoiding rotation; scheduling rest or nap periods; and perhaps even favouring chronotype “owls” for night-shift work.10

The relationship between sleep and circadian regulation is complex and not well understood. It is known that the “sleep homeostat”, which monitors the need for sleep based on a person’s prior sleep history, can operate independently of the circadian clock. There is nevertheless an interaction between sleep and circadian regulation, as evidenced by CRSDs and the effects of orexins, which are functionally linked to the SCN and involved in mediating circadian suppression of rapid eye movement (REM) sleep.

The clinical relevance of these complexities is that sleep disorders may arise from different combinations of sleep and circadian abnormalities. CRSDs are mainly abnormalities in the timing of sleep and are classified broadly as “extrinsic” or “intrinsic”. Extrinsic disorders include jet lag and shift work sleep disorder. Intrinsic disorders include advanced and delayed sleep phase syndromes, free running disorder, and irregular sleep–wake disorder. Intrinsic CRSDs are of interest, not least because a better understanding of the relationship between circadian and sleep regulation may lead to more effective treatment of insomnia — a frequent complaint in primary health care.

Most serious mental illnesses are associated with sleep disturbance, and some, especially affective disorders, are also associated with circadian abnormalities. It remains to be seen whether circadian abnormalities are a primary or secondary manifestation in affective disorders, but there is evidently a relationship between mood and circadian regulation. Mood disorders are associated with a disturbance of circadian rhythms, and disruption of circadian rhythms is associated with a disturbance of mood.11 Under these circumstances, effective circadian resetting to a normal sleep–wake cycle, using methods such as artificial light, chronobiotic medication (antidepressants, melatonin agonists) and sleep deprivation, may be useful in the treatment of mood disorders.

Chronotherapy considers the impact of circadian variation on diseases and treatment side effects. Applied to pharmacotherapy, it recognises that optimal treatment depends not only on the dose but also on the time of day that medication is given. Medications for asthma, allergies, cardiovascular disease, pain and cancer can produce better results with fewer side effects when given at particular times.12 The kinetics of antihypertensive medication vary with circadian rhythms in gastrointestinal pH, emptying and motility, and blood flow (“chronokinetics”). So-called “chronodynamic” effects can be seen with the use of non-steroidal anti-inflammatory drugs (NSAIDs) to treat arthritis. NSAIDs are more effective for osteoarthritis (symptoms worse at night) when taken around noon, but are more effective for rheumatoid arthritis (symptoms worse in the morning) when taken after the evening meal.

Although recognised since antiquity, the scientific study of circadian and other biological rhythms, now referred to as “chronobiology”, did not become firmly established until the second half of the 20th century. There is now a burgeoning literature in the field and, specifically with regard to circadian rhythms, an expectation of useful clinical applications from further progress in understanding. Research conducted in the past 40 years has not only dispelled any remaining mysticism but has also provided a clear justification for teaching on chronobiology and chronotherapy to be included in medical curricula.