Melatonin As A Marker For Circadian Phase Position

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Determination of circadian phase, normal and pathological, can be done in a number of ways. The easiest but least reliable way is to use the timing of sleep (sleep offset is usually more reliable than sleep onset). Other physiological measures are more reliable but are sometimes difficult to assess, such as core body temperature and cortisol. There are also disagreements over how these data should be collected, specifically whether or not it is necessary or even desirable to use a constant routine in which semi-recumbent subjects are sleep deprived and fed isocalorically for one or two days (26-27).

The circadian rhythm of melatonin production turns out to be perhaps the best marker for circadian phase. Its standard deviation is less than that of the temperature rhythm (28). A constant routine is not necessary for its assessment, although sample collection should be done under dim light (<30 lux). It can be assessed using blood, saliva or urine, although the latter is difficult to collect in intervals shorter than 1-2 hours, and the more frequent the collection intervals the more highly resolved the phase marker.

Frequent sampling around the time of the melatonin onset may turn out to be the most useful of all of the markers for circadian phase. The melatonin onset is a clearly demarcated event (Figure 2). With 30-minute sampling, the standard deviation of the dim light melatonin onset (DLMO) is less than its sampling interval (28). The DLMO usually occurs before bedtime; consequently, there is little or no disturbance of sleep.

Confining measurement of the endogenous melatonin profile to the DLMO has been criticized because assessment of the amplitude of the melatonin profile is not obtained. However, there are few if any reasons to assess amplitude of the melatonin profile. It is questionable that the melatonin peak reflects the amplitude of the ECP (29); there is even some doubt that the temperature rhythm reflects ECP amplitude. Furthermore, amplitude differences in melatonin (or even in the ECP) have yet to be conclusively shown to be important.

Confining measurement of the endogenous melatonin profile to the DLMO has been criticized because it ignores the melatonin offset. However, while it appears that the melatonin offset may be regulated by a separate oscillator in rats, this has not been established in humans (30). Indeed, if there is a separate offset oscillator in humans it appears to be so tightly coupled to the onset oscillator that there appears to be no need to measure both. Given the choice between the onset and the offset, the onset is much preferred, since the offset is confounded by biochemical factors that

Cadian Rhythm
Figure 2. Dim light melatonin onsets (DLMOs) are shown from a patient with winter depression before (closed circles) and after (open squares) successful treatment with afternoon melatonin. An advance in cir-cadian phase accompanied her clinical remission, as expected.

appear to contribute to a higher standard deviation. The actual time that melatonin production ceases is usually a few hours before wake-up time and therefore melatonin half-life will affect the time when circulating levels fall to daytime values (31); in other words, accurate measurement of the true offset requires middle-of-the-night sampling with its attendant disturbance of sleep. It is possible that some pathologies will be evident in the dim light melatonin offset (DLMOff) and not in the DLMO. However, to date no conclusive evidence has been presented suggesting that pathological changes in the DLMOff (not also reflected in the DLMO) predict response to phase-resetting treatment.

Light appears to have identical effects on shifting the phase of the melatonin onset and offset, at least when assessed the day after the last light pulse (32). To be conservative, however, assessments should be ,controlled for time of the year, in case it turns out that there are significant seasonal differences in melatonin duration (33). In short, there seems to be no reason at the present time not to confine assessment of circadian phase to the DLMO, particularly if practical considerations are important.

This does not mean that more information cannot be obtained by assessing other rhythms. If there are phase differences between the melatonin profile and other circa-dian rhythms, the melatonin profile in all likelihood most accurately reflects the phase of the ECP, as it is least susceptible to masking and other influences that could distort its waveform. It also appears to be tightly coupled to the ECP (34). Nevertheless, the phase relationships between overt circadian rhythms (particularly between the sleep/wake cycle and the DLMO) are often of interest (35).

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