Progress in Neuro-Psychopharmacology and Biological Psychiatry
Review articleDim light melatonin onset (DLMO): A tool for the analysis of circadian phase in human sleep and chronobiological disorders
Section snippets
Assessment of the endogenous circadian pacemaker
During the past decade, considerable progress has been made in determining the molecular components of the biological clock (Saper et al., 2005). These molecular mechanisms are universally present in all cells and consist of gene-protein–gene feedback loops in which proteins down regulate their own transcription and stimulate the transcription of other clock proteins. Although anchored genetically, circadian rhythms are synchronized (entrained) by and maintain certain phase relationships to
Melatonin measurement in body fluids
The threshold of melatonin concentration that differentiates nighttime from daytime values is difficult to determine because, as noted above, there exists a subpopulation of low melatonin producers whose peak nighttime values are markedly smaller than those of normal individuals. Lewy et al. (1999) recommended 2 pg/ml as the lowest plasma threshold at which the daytime and nighttime values could be differentiated. The earliest reported assays of plasma melatonin were based on gas
Melatonin synthesis regulation: role of light
The circadian pattern of melatonin secretion is abolished by lesions of the SCN (Claustrat et al., 2005). The environmental 24 h LD cycle acts as the predominant Zeitgeber that regulates melatonin synthesis (Scheer and Czeisler, 2005). The circadian activity of the SCN is synchronized to the LD cycle by light mainly through a monosynaptic retinohypothalamic tract (RHT) originating from the ganglion cell layer in the retina. Animal studies have now identified the neural pathway which connects
Entrainment of melatonin rhythm by LD cycle
Drugs that influence the circadian apparatus are referred to as “chronobiotics” with melatonin being their prototype (Cardinali et al., 2006). Indeed, melatonin secretion is an “arm” of the biologic clock in the sense that it responds to signals from the SCN. In particular the timing of the melatonin rhythm indicates the status of the clock, both in terms of phase (i.e., internal clock time relative to external clock time) and of amplitude. Further, melatonin is also a chemical code for the
Phase response curve (PRC) to melatonin vs. PRC to light
A PRC is constructed by administering a synchronizing stimulus during different times (or circadian phases) and then evaluating its effect on the phase of the circadian clock. PRC's generally depict the sensitivity of the circadian clock and the relationship between various stimuli or Zeitgebers and the circadian rhythms (Fig. 1). A schematic PRC to exogenous melatonin or to light illustrates that the timing of melatonin or light administration is crucial for achieving the magnitude and
DLMO in circadian rhythm sleep disorders
The use of DLMO has been recommended as a method for assessing the phase of the circadian pacemaker in patients suffering from sleep or mood disorders involving a chronobiological component (Table 2). The abnormal timing of the DLMO seen in these patients provides a clue for the optimal timing of treatment. Sleep displacements have been found to cause phase shifts in DLMO. VanCauter et al. (1998) reported an acute 2 h phase advance in the onset, and a 1 h phase advance in the offset of the
DLMO in mood disorders
The DLMO is not only useful in phase typing circadian phase sleep and mood disorders, but also is helpful in assessing the response to bright light treatment (Cajochen et al., 2005). Circadian rhythm abnormalities are implicated in the pathogenesis of mood disorders (Baumann et al., 2004, Carskadon et al., 2004, Klerman, 2005, Srinivasan et al., in press). Abnormalities of phase positions of cortisol, CBT and melatonin rhythms in depressed patients have all been documented. Salivary melatonin
Conclusions
The DLMO test is one of the most reliable markers of the phase of the circadian pacemaker and is consequently becoming popular as an effective measurement for studies of sleep phase delay. Through the use of the DLMO marker, the phase advance and phase delay zones of the melatonin PRC can be differentiated, thus permitting a diagnosis of whether an individual is entrained to the 24-h LD cycle or is free running. Hence the DLMO is being used to study the phase typing in patients with a
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This article is dedicated in honor of the memory of Dr. L. Kayumov, who passed away in an unfortunate circumstances. Dr. Kayumov was a dedicated sleep researcher and a great mentor.