Elsevier

Sleep Medicine Reviews

Volume 18, Issue 4, August 2014, Pages 333-339
Sleep Medicine Reviews

Clinical review
Why the dim light melatonin onset (DLMO) should be measured before treatment of patients with circadian rhythm sleep disorders

https://doi.org/10.1016/j.smrv.2013.12.001Get rights and content

Summary

Treatment of circadian rhythm sleep disorders (CRSD) may include light therapy, chronotherapy and melatonin. Exogenous melatonin is increasingly being used in patients with insomnia or CRSD. Although pharmacopoeias and the European food safety authority (EFSA) recommend administering melatonin 1–2 h before desired bedtime, several studies have shown that melatonin is not always effective if administered according to that recommendation. Crucial for optimal treatment of CRSD, melatonin and other treatments should be administered at a time related to individual circadian timing (typically assessed using the dim light melatonin onset (DLMO)). If not administered according to the individual patient's circadian timing, melatonin and other treatments may not only be ineffective, they may even result in contrary effects.

Endogenous melatonin levels can be measured reliably in saliva collected at the patient's home. A clinically reliably DLMO can be calculated using a fixed threshold. Diary and polysomnographic sleep-onset time do not reliably predict DLMO or circadian timing in patients with CRSD.

Knowing the patient's individual circadian timing by assessing DLMO can improve diagnosis and treatment of CRSD with melatonin as well as other therapies such as light or chronotherapy, and optimizing treatment timing will shorten the time required to achieve results.

Section snippets

Sleep and circadian timing

Sleep is defined as a natural state characterized by a reduction in voluntary motor activity, a decreased response to stimulation and a stereotypic posture [1]. Despite the immense amount of sleep research, some of the function(s) of sleep remain elusive. To better understand how humans achieve consolidated sleep (and wakefulness), a two-process model of human sleep regulation has been proposed [2], [3]. This model includes a homeostatic sleep drive (process S) determined by recent sleep–wake

Diagnosing circadian rhythm sleep disorders

CRSD are a group of sleep–wake disorders in which patients have problems with the timing of sleep due to a misalignment between the timing of the internal biological clock and the timing of the desired sleep episode [12]. To state this in a simplified way, the patient cannot sleep when sleep is expected or needed. Currently seven distinct CRSD are recognized in the international classification of sleep disorders (ICSD) [13]. These are 1) time zone change (jet lag) syndrome, 2) shift work sleep

Treatment of circadian rhythm sleep disorders

CRSD can be treated with measures such as improving sleep hygiene, strengthening time-cues, chronotherapy, bright light, or melatonin as a chronobiotic drug [25], based on three pillars: 1) strengthening time clues (zeitgebers), 2) adequately timed bright light and 3) adequately timed exogenous melatonin [26], [27]. The goal of all treatments for CRSD is to shift the timing of the circadian system so that the patient can sleep at a more appropriate time of day. Thus, for patients with DSPD, the

Melatonin assay

Analytical techniques for the detection of melatonin levels in biospecimen are becoming more sophisticated. Limit of quantification (LOQ, or the lowest level of melatonin that can be measured with accuracy) is especially important to determine the phase of the endogenous circadian pacemaker using melatonin. Bioassays, radioimmunoassay (RIA) and gas chromatography mass-spectrometry were among the first techniques that could measure melatonin with a low LOQ using blood or plasma [46], [47], [48],

DLMO determination

Under normal conditions melatonin concentration increases during the evening, levels continue to increase during the sleep period, and begin to decline after mid-sleep [58]. During the day, melatonin is not produced in measurable quantities. However, in patients with CRSD or those with certain syndromes such as Smith-Magenis, the typical pattern of melatonin secretion may be altered or even inverted [59], [60]. A typical melatonin curve is displayed in Fig. 1.

In healthy young individuals who

Clinical experience

The Centre for Sleep-Wake Disturbances and Chronobiology of the Gelderse Vallei Hospital sees about 1500 patients annually with possible circadian-rhythm sleep–wake disturbances. In this section we present our clinical experience diagnosing and treating such patients.

Intake and preliminary investigation begins with an on-line questionnaire. If the response suggests a potential CRSD, a home test kit containing Salivettes® and instructions is sent to the patient to collect samples to assess DLMO

Conclusion

DLMO is a clinically relevant tool for the diagnosis and treatment of CRSD, and is used to discriminate CRSD from other non-circadian sleep disturbances. In the ideal situation, it should be assessed to determine the phase of the circadian rhythm before treatment commences to prevent adverse phase shifting effects and to speed treatment effects. While DLMO assessment is not the standard practice in most countries, there is accumulating evidence that DLMO measurement strongly benefits patient

Acknowledgements

The authors report no conflicts of interest related to the present paper.

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