Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 1 11

www.elsevier.com/locate/pnpbp

Review article
Dim light melatonin onset (DLMO): A tool for the analysis of circadian
phase in human sleep and chronobiological disorders
Seithikurippu R. Pandi-Perumal a,, Marcel Smits b , Warren Spence c,f ,
Venkataramanujan Srinivasan d , Daniel P. Cardinali e , Alan D. Lowe f , Leonid Kayumov f,
a
Comprehensive Center for Sleep Medicine, Department of Pulmonary, Critical Care, and Sleep Medicine, Mount Sinai School of Medicine,
1176 5th Avenue 6th Floor, New York, NY 10029, USA
b
Gelderse Vallei Hospital, Department of Neurology and Sleep Disorders, Box 9025, 6710 HN Ede, The Netherlands
c
Centre for Addiction and Mental Health, 1071-A-1, ARF Division, 33 Russell Street, Toronto, Ontario, Canada M5T-1R8
d
Department of Physiology, School of Medical Sciences, University Sains Malaysia, 16150 Kubang Kerian, Kota Bharu, Kelantan, Malaysia
e
Departamento de Fisiologa, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, piso 7, 1121 Buenos Aires, Argentina
f
Department of Psychiatry, University of Toronto, and Sleep and Neuropsychiatry Institute, 4235 Sheppard Avenue East,
Suite 208, Scarborough ON, Canada M1S 1T7
Received 23 March 2006; received in revised form 23 June 2006; accepted 26 June 2006
Available online 1 August 2006

Abstract

The circadian rhythm of melatonin in saliva or plasma, or of the melatonin metabolite 6-sulphatoxymelatonin (aMT6S) in urine, is a defining
feature of suprachiasmatic nucleus (SCN) function, the endogenous oscillatory pacemaker. A substantial number of studies have shown that,
within this rhythmic profile, the onset of melatonin secretion under dim light conditions (the dim light melatonin onset or DLMO) is the single
most accurate marker for assessing the circadian pacemaker. Additionally, melatonin onset has been used clinically to evaluate problems related to
the onset or offset of sleep. DLMO is useful for determining whether an individual is entrained (synchronized) to a 24-h light/dark (LD) cycle or is
in a free-running state. DLMO is also useful for assessing phase delays or advances of rhythms in entrained individuals. Additionally, it has
become an important tool for psychiatric diagnosis, its use being recommended for phase typing in patients suffering from sleep and mood
disorders. More recently, DLMO has also been used to assess the chronobiological features of seasonal affective disorder (SAD). DLMO marker is
also useful for identifying optimal application times for therapies such as bright light or exogenous melatonin treatment.
2006 Elsevier Inc. All rights reserved.

Keywords: Circadian rhythms; Delayed sleep phase syndrome; Dim light melatonin onset; Light/dark cycle; Melatonin; Mood disorders; Seasonal affective disorder

Contents

1. Assessment of the endogenous circadian pacemaker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

2. Melatonin measurement in body fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Melatonin synthesis regulation: role of light . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
4. Entrainment of melatonin rhythm by LD cycle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
5. Phase response curve (PRC) to melatonin vs. PRC to light . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
6. DLMO in circadian rhythm sleep disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Corresponding author. Tel.: +1 212 241 5098; fax: +1 212 241 4828.
E-mail address: pandiperumal@gmail.com (S.R. Pandi-Perumal).

This article is dedicated in honor of the memory of Dr. L. Kayumov, who passed away in unfortunate circumstances. Dr. Kayumov was a dedicated sleep researcher
and a great mentor.

0278-5846/$ - see front matter 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.pnpbp.2006.06.020
2 S.R. Pandi-Perumal et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 111
7. DLMO in mood disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. 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-proteingene 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 exog-
enous factors (environmental time cues or Zeitgebers), especially
the sleep portion of the light/dark (LD) schedule. The rhythms
will persist with a period different from 24 h when external time
cues are suppressed or removed, such as when the organism is in
complete social isolation or subjected to constant light or
darkness (Saper et al., 2005).
Cellular clocks are governed in mammals by a master time-
keeping system located in the anterior hypothalamus (SCN).
The SCN is the pacemaker that generates a 24 h periodic
signal which is synchronized to exactly 24 h by external
sychronizers (or Zeitgebers) (Saper et al., 2005). Average
human endogenous period (tau) is thought to vary between
24.2 h (Czeisler et al., 1999) and 24.9 h (Sack et al., 2000). The
circadian component of the sleep/wake cycle is regulated by the
circadian pacemaker (Monk, 2005). The administration of the
pineal product melatonin has been found to stabilize sleep/wake
timing even in the blind whose circadian systems are not
entrained to the 24 h day (Lockley et al., 2000; Sack et al., 1991,
2000). Melatonin administration induces differences in phase of
circadian rhythms, either by accelerating (phase advance) or
slowing down (phase delay) human circadian rhythms with the
direction of shift being dependent upon the time of adminis-
tration (Lewy et al., 1998).
As research on the circadian system has progressed, several
procedures have been developed to document the role of the
circadian pacemaker in the regulation of physiological process-
es. For instance, the cyclic rise and fall of cortisol and melatonin
have been used as markers of the circadian phase for measuring
the effects of light exposure (Klerman, 2005). Parameters of
sleepwake cycle have also been used as phase markers in
humans (Martin and Eastman, 2002). Plasma melatonin has
been used for years to assess the circadian phase. Melatonin
levels in plasma begin to increase before sleep and peak the first
part of the night. Since Lewy's discovery that bright light can
suppress or mask nighttime melatonin production (Lewy et
al., 1980), it has become recognized that masking is a problem
for all marker rhythms. Further, it is not always easy to answer
the question of whether there are multiple oscillators for a
given cyclic phenomenon or whether one is more reliable than
others.
8
9
9
Circulating melatonin levels are often preferred as a
circadian marker because they are comparatively robust in the
presence of various external influences. For example, while
excessive carbohydrate intake can produce significant changes
in core body temperature (CBT) and heart rate, melatonin
concentration remains essentially uninfluenced by this factor
(Krauchi et al., 2002).
One variable which does affect melatonin production however
is environmental illumination. It has been recommended that in
studies in which melatonin is used as a circadian phase marker,
exposure to dim light should be initiated 12 h before the earliest
melatonin onset (Lewy et al., 1984; Lewy, 1999). This implies
that dim light should be started at 17:00 h and blood sampling
should be started around 18:00 h. The level of illumination
currently recommended for sampling is 10 lx. Absolute darkness
appears to have no advantage over dim light for minimizing the
suppressant effect of bright light on melatonin production. The
plasma levels of the major melatonin metabolite, aMT6S, have
also been employed to measure DLMO (Bojkowski et al., 1987).
The fact that melatonin onset is not affected by biochemical
and physiological confounding factors accounts for its compar-
atively greater reliability to measure circadian phase position
(Lewy, 1999; Lewy et al., 1999). There may also be individual
differences to be accounted for. Human plasma melatonin levels
during the day are usually lower than 10 pg/ml, whereas during
nighttime values normally exceed 40 pg/ml. In low melatonin
producers, plasma levels are considerably lower. Therefore, a
2 pg/ml plasma threshold is often recommended for measuring
DLMO (Lewy et al., 1999). Another possibility is to employ the
procedure recommended by Voultsios et al. (1997) for deter-
mining a threshold, i.e., the mean of 3 points plus two times the
SD of those 3 points.
2. 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) recom-
mended 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 chroma-
tography/mass spectrometry (GCMS) but were later replaced by
more specific and sensitive radioimmunoassays, suitable to be
used in a clinical environment (Lewy et al., 1999).
Leibenluft et al. (1996) employed salivary samples to measure
DLMO and proposed this measurement as the most practical and
reliable method for assessing the circadian phase. The correlation
coefficient between plasma and salivary assessment of DLMO
 S.R. Pandi-Perumal et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 111
was 0.93 (Leibenluft et al., 1996). A salivary melatonin assay
described by Voultsios et al. (1997) was found to have the
sensitivity and accuracy comparable to that of GCMS assay. This
has contributed to the rapid adoption of salivary testing as the
preferred method for sampling melatonin, inasmuch as it is
relatively non-invasive and more acceptable to patients (Table 1).
An additional advantage of the method is that, with proper
training, the patients themselves can collect the samples at home
and deliver them to the laboratory for assay. In more recent studies
salivary sampling has become the primary measurement for
assessing physiological levels of melatonin, especially in
longitudinal investigations in which repeated measures are
needed (Table 2). It must be noted that melatonin levels and
consequently DLMO obtained in a sleep laboratory may differ
from those obtained in free field, i.e. at home (Roach et al., 2001;
Harada, 2004; Kawinska et al., 2005). Comprehensive field
studies on normal values of DLMO in healthy adults have not yet
been published.
In the Dutch national referral centre for sleepwake distur-
bances and chronobiology, headed by one of the authors of this
article, salivary DLMO is measured every year in about 1000
patients with a possible circadian rhythm disorder. In adults
DLMO is defined as the time at which a salivary concentration
of melatonin of 4 pg/ml is reached (Nagtegaal et al., 1998a,b,
Table 1
Procedures for Dim Light Melatonin Onset (DLMO) measurements in saliva
1. During the saliva collection period consumption of bananas, alcoholic
beverages, or coffee are prohibited.
2. During the time of collection the subject must remain in dim light (10 lx) from
1 h prior to scheduled saliva collection. Curtains in the room must remain
closed. Watching TV is permitted.
3. Fifteen minutes before every collection of saliva the subject must rinse his
mouth with water.
4. Eating is permitted after saliva collection (except for the food
described at 1).
5. Subjects must not brush their teeth during the saliva collection period.
6. Nighttime saliva collection must only be done under dim light conditions.
7. Physical activities during the collection period are to be avoided as much as
possible.
Partial melatonin curve:
Indications:
In patients older than 16 years who are suspected of having delayed sleep
phase syndrome: saliva is to be collected hourly between 9 p.m. and 1 a.m.
In patients older than 16 years who are suspected of advanced sleep phase
syndrome: saliva is to be collected hourly between 7 p.m. and 11 p.m.
In children younger than 13 years who are suspected of delayed sleep phase
syndrome: saliva is to be collected hourly between 7 p.m. and 11 p.m.
In children younger than 13 years who are suspected of advanced sleep
phase syndrome: saliva is to be collected hourly between 4 p.m. and 9 p.m.
In children and adults suspected of irregular sleepwake rhythm / melatonin
rhythm: saliva is to be collected hourly between 8 and 12 p.m., once a week
for 4 weeks
If the approximate time of the DLMO cannot be estimated, all subjects
(whether they are adults or children) should start sampling at 1800 and
continue until habitual bedtime.
24-h melatonin curve:
Indications:
When the partial melatonin curve is inconclusive
In patients with a suspected free running rhythm (especially in blind people)
3
2000; Smits and Nagtegaal, 2000; Wieringer et al., 2001; Smits
et al., 2002) and is considered to be normal when it occurs
between 19:30 and 22:00 h. In children between 6 and 12 year
DLMO is considered to be normal if it occurs between 19:00
and 21:00 h (Smits et al., 2001, 2003; Heijden et al., 2005).
3. 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) orig-
inating from the ganglion cell layer in the retina. Animal studies
have now identified the neural pathway which connects the SCN
with the pineal gland. This has been shown to include the
hypothalamic paraventricular nucleus, and projections of fibers
through the medial forebrain bundle and reticular formation to cells
of the intermediolateral columns of the cervical spinal cord.
Additionally, preganglionic sympathetic fibers project upward to
the superior cervical ganglia (SCG). In the final step of this
transmission postganglionic sympathetic fibers from the SCG
reach the pineal gland and release norepinephrine (NE) (Claustrat
et al., 2005).
Activation of pineal -adrenergic receptors results in an
increase of melatonin synthesis; 1-adrenergic receptors are also
detectable in the pineal gland and potentiate -adrenergic receptor
activity (Claustrat et al., 2005). During the light phase, the SCN
electrical activity is high and under these conditions pineal NE
release is inhibited. Conversely, SCN activity is inhibited during
darkness and NE release in the pineal gland augments. -
adrenergic blockers have been shown to suppress the nocturnal
synthesis and secretion of melatonin in humans, suggesting a
similar regulation of pineal melatonin production (De Leersnyder
et al., 2003). If the SCN is activated by light at night, NE release in
the pineal gland is inhibited. However, there is a lack of
correlation between the suppressant effect of light on melatonin
synthesis and the pharmacological effect of the -adrenergic
blocker propranolol (Mayeda et al., 1998), thus suggesting that
other non-adrenergic mechanisms may be involved.
Melatonin secretion is suppressed by ambient light intensities
typically encountered outdoors (i.e., ranging from 3000 to
100,000 lx) but, under certain circumstances, even lower inten-
sities (ranging from 100 to 300 lx) can have a suppressant effect on
melatonin (Duffy and Wright, 2005). Light-induced suppression
of pineal melatonin synthesis and secretion in humans has peak
sensitivity at short wavelength light (446477 nm) (Brainard
et al., 2001; Kayumov et al., 2005).
Originally, it was thought that the LD cycle was relatively
less significant when compared to other social cues in resetting
the human circadian rhythms. Following the discovery by Lewy
et al. (1980) that bright light of 2500 lx or greater suppresses
melatonin secretion, it has been repeatedly found that human
circadian rhythms are synchronized by the 24 h LD cycle. This
opened up a new area not only for studying the synchronization
of human circadian systems but also for understanding the
4 S.R. Pandi-Perumal et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 111
Table 2
Studies using DLMO as a tool for assessing circadian phase position, chronobiological sleep disorders and mood disorders
Condition or Group
WD
WD
WD
WD
Effect of morning BLT
Effect of sleep displacement
(2 h phase advance)
Melatonin (0.5 mg)
administration in
normal subjects
SAD
BLT (2500 lx) in SAD for 2 h
Bipolar affective disorder
Non-seasonal depression
DSPS
DSPS
DSPS
Effect of BLT (2500 lx)
Effect of sleep displacement
Children with idiopathic chronic
sleep onset insomnia
Chronic whiplash syndrome
CFS
Night-shift workers
Saliva DLMO study in
the elderly
Children with idiopathic
chronic sleep onset insomnia
Effect of exercise on circadian
melatonin rhythm
Effect of bedtime on DLMO
Effect of combination of evening
melatonin and BLT
Effect of different light
wavelengths
on salivary DLMO
Effect of early evening melatonin 110 (aged 612 years)
administration on chronic sleep
onset insomnia as predicted by
DLMO
N Results or conclusion(s) Reference
8 patients, 7 controls Phase delay of DLMO in winter depressives as compared to controls. Lewy et al. (1984)
Intrinsic abnormality of circadian rhythm noted in winter depressives.
8 patients, 7 controls Application of morning bright light phase-advanced DLMO Lewy et al. (1985)
6 Phase advancement of DLMO Lewy et al. (1987)
8 patients, 5 controls Phase delay of DLMO in WD patients Sack et al. (1990)
8 patients, 5 controls Morning bright light phase-advanced melatonin onset in patients Sack et al., (1990)
but not in controls
6 No phase shift of the DLMO Hoban et al. (1991)
9 Morning melatonin phase delays circadian rhythms; Lewy et al. (1992)
afternoon/evening melatonin phase advances circadian rhythms
6 patients, 6 controls Phase delay of circadian rhythms in SAD compared to controls Dahl et al. (1993)
6 SAD patients Phase-advanced DLMO in SAD patients Dahl et al. (1993)
12 bipolar depressives Salivary DLMO correlates with plasma DLMO Leibenluft et al. (1996)
(correlation coefficient = 0.93)
8 patients, 8 controls No phase differences in DLMO between healthy and depressed subjects Gordijn et al. (1998)
30 patients When given 5 h before DLMO melatonin advanced DLMO by 98 min. Nagtegaal et al. (1998)
Conclusion: to measure DLMO in DSPS patients is important for both
diagnosis and therapy.
13 patients Melatonin (0.33 mg) administered daily 1.56.5 h prior to DMLO for Mundey et al. (2005)
4 weeks advanced the circadian phase of endogenous melatonin and
sleep in a phase dependent manner.
20 patients Melatonin ameliorated some symptoms of subjective and objective Kayumov et al. (2001)
measures without any adverse effects in 4-week treatment period
12 healthy subjects Morning light phase-advanced DLMO more than evening light Gordijn et al. (1999)
12 healthy subjects 3 h phase advance of sleep displacement did not shift DLMO; Gordijn et al. (1999)
3 h phase-delay of sleep caused phase-delay of DLMO
40 patients Melatonin advances mean lights off time by 34 min, sleep onset Smits et al. (2001)
by 63 min and increases total sleep time by 41 min
81 patients DLMO was delayed in chronic whiplash syndrome patients Wieringer et al. (2001)
(mean DLMO: 23:20 h). Melatonin administered 5 h before DLMO
advanced DLMO and sleepwake rhythm.
29 patients In CFS patients with DLMO later than 22:00 h melatonin treatment, Smits et al. (2002)
administered 5 h. before DLMO, decreased fatigue more than in
CFS patients with DLMO between 21:30 and 22:00 h.
67 (median age 22 years) DLMO was measured before and after nightshifts Crowley et al. (2003)
(baseline and final). Various combinations of interventions like
wearing sunglasses during the commute home, creating a dark bed
room, and adhering to a regular daytime sleep schedule starting
soon after the night shift reduced circadian misalignment
85 (over 65 years) The correlation coefficient for saliva and serum Gooneratne et al. (2003)
melatonin was r = 0.659.
62 patients Melatonin advanced DLMO by 1:22 h, advanced sleepwake rhythm Smits et al. (2003)
and improved health status
18 healthy subjects Exercise phase-delayed DLMO, thus helping to facilitate circadian Barger et al. (2004)
adaptation to schedules requiring a phase delay in the sleepwake cycle
10 healthy subjects No significant correlation between morningness/eveningness Burgess and Eastman
and the shift of the DLMO. No significant sex difference in (2004)
the shift of the DLMO; melatonin rhythm following the late
bed night was delayed.
9 healthy young subjects A single light pulse (5000 lx for 3 h) caused phase delay of DLMO. Wirz-Justice et al. (2004)
Melatonin administration caused a phase advance of DLMO.
Combination of evening melatonin and light was additive in
their phase shifting effects.
42 healthy subjects Shorter wavelengths caused greatest melatonin onset Wright et al. (2004)
(by 40 to 65 min)
The efficacy of early evening melatonin treatment to advance van der Heijden et al.
sleep onset could be predicted by the circadian pace marker DLMO (2005)
in children with chronic SOI.
 S.R. Pandi-Perumal et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 111 5

Table 2 (continued )
Condition or Group N Results or conclusion(s) Reference
ADHD 87 patients DLMO is delayed in ADHD children with chronic idiopathic sleep Van der Heijden et al.
onset insomnia. (2005)
Conclusion: chronic insomnia in ADHD children with chronic sleep
onset insomnia is caused by a circadian rhythm disorder.
CFS 38 patients In CFS patients with DLMO later than 21:30 h melatonin improves van Heukelom et al.
quality of life scores, physical functioning, energy/vitality, bodily pain (2006)
and general health perception.
Abbreviations: DLMO: Dim light melatonin onset; WD: Winter depression; BLT: Bright light treatment; SAD: Seasonal affective disorder; DSPS: Delayed sleep
phase syndrome; CFS: Chronic fatigue syndrome; ADHD: Attention-deficit/hyperactivity disorder; lx: Lux.

pathophysiology of certain chronobiological disorders such as
bipolar affective disorder (Buysse, 2005; Harper et al., 2005).
Bright light shifts the phase of melatonin rhythm with
morning hours being associated with phase advances in the
rhythm and evening hours with phase delays (Duffy and Wright,
2005). Lockley et al. (2003) found that exposure of human
volunteers to 6 h of monochromatic blue light (460 nm)
produced a circadian delay which was two-fold as great as that
produced by an equivalent exposure to 555 nm light. Moreover,
melatonin secretion was suppressed twice as much by 460 nm
light as compared to 555 nm light. This study confirmed that
melatonin production and suppression in humans is primarily
due to blue wavelength photoreceptors that are distinct from the
photopic visual system (which is primarily sensitive to longer
wavelengths). The mechanism by which circadian rhythms are
regulated by shorter wavelength sensitive photoreceptors was
assessed by Cajochen et al. (2005) in phase shifting and mela-
tonin suppression studies. Their findings suggested that photo-
receptors, which may contain melanopsin as a photopigment,
are involved in several functions, including the regulation of
human alerting responses to light, thermoregulation and heart
rate.
There are substantial individual variations in sensitivity to
the intensity of light required for suppressing melatonin
secretion. This is determined not only by environmental factors
but also by genetic factors as well. Factors such as the intensity
of light applied and duration of exposure seem to determine the
level of melatonin suppression. Lewy et al. (1980) showed that
light with an intensity of 2500 lx, when administered for 2 h,
could suppress the nocturnal melatonin secretion to the low
circulating levels seen during daytime. However, partial sup-
pression of melatonin secretion can be achieved with lower
intensities of light (200300 lx) administered for 30 min
(Bojkowski et al., 1987). Light intensities of 100 lx have also
been shown to suppress melatonin production under certain
circumstances (Boivin et al., 1996).
4. 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 night: the longer the
night, the longer the duration of its secretion. In most species,
this pattern of secretion serves as an internal time cue for other
rhythms which are governed by seasonal changes (Claustrat et
al., 2005).
Melatonin may help the endogenous circadian pacemaker to
discriminate the dark phase of the 24-h LD cycle from the
sporadic episodes of darkness (Lewy et al., 1996). A study
undertaken in Antarctica suggests that a structured social
routine in a dim light environment is sufficient to synchronize
melatonin to a 24 h cycle (Midwinter and Arendt, 1991). In this
context, it is interesting to note that a minority of permanent
night shift workers show a shift in peak in melatonin production
during the day which eventually mirrors the former nocturnal
profile. Zeitzer et al. (2000) demonstrated that humans are
highly responsive to phase delaying effects of light during early
biological night. In a study of 30 permanent night nurses who
worked for 39 consecutive nights (midnight to 08:00 h), 5
nurses underwent phase delay adaptation and had a realignment
of their melatonin rhythm and sleep, 22 were non-shifters and 3
exhibited an advanced rhythm (Dumont et al., 2001). This study
reveals that while the circadian rhythms of some night shift
workers are capable of phase shift reversals, most individuals do
not exhibit this radical change. A better circadian adaptation can
occur when night shift workers receive less morning or after-
noon light (Burgess et al., 2002). Exposure to room lighting of
about 180 lx for 3 consecutive days in the morning has been
shown to significantly phase advance the human circadian
phase maker (Boivin et al., 1996).
Zeitzer et al. (2000) found that room light intensity influenced
the human circadian pacemaker when applied during the first
6.5 h of biological night. Plasma melatonin concentration became
suppressed in a dose-dependent manner during the single 6.5 h
light stimulus, administered from 23.00 h to 05.30 h. While low
illuminance did not evoke much change, bright room light or
higher illuminances completely suppressed plasma melatonin. It
was further noted that the acute response of melatonin to
increasing illuminance occurred in a stepwise manner with
suppression of melatonin at illuminations greater than 200 lx and
minimal suppression below 80 lx. Bright room light (above
500 lx) caused an apparent saturating phase shift of the endog-
enous circadian melatonin rhythm (Zeitzer et al., 2000). The
phase resetting response to light and acute suppressive effects of
light on plasma melatonin followed a dose response curve.
Exposure to a single 6.5 h episode of 100 lx light generated half of
the response observed for a stimulus that was nearly 100 fold
6 S.R. Pandi-Perumal et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 111

brighter (9000 lx) (Zeitzer et al., 2000). A photic stimulus in the
early subjective night will delay the timing of the clock while light
exposure in the late subjective night and early subjective morning
will advance the timing of the clock (Duffy and Wright, 2005).
Light exposure at either time will induce a suppression of
melatonin production. Whether this melatonin suppression is
necessary to induce a phase delay is not yet clear since phase shifts
occur during daytime when melatonin secretion is almost nil
(Khalsa et al., 2003). The DLMO studies undertaken by Wirz-
Justice et al. (2004) confirmed the finding that suppression of
melatonin does not appear to be a prerequisite for phase shifting
the human circadian pacemaker. In that study administration of a
single light pulse (5000 lx for 3 h) or a single melatonin pill (5 mg)
at 20:40 h caused phase delay or phase advance of DLMO,
respectively, when assessed 24 h later. Combinations of both
interventions caused additive effects. The Zeitgeber effect of
melatonin was shown to be as effective as that of bright light
(Wirz-Justice et al., 2004). A number of studies employing
DLMO as a tool for assessing circadian phase position, chrono-
biological sleep disorders and mood disorders are summarized in
Table 2.
5. 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
direction of subsequent phase shift (Burgess et al., 2002; Lewy
et al., 1998; Minors et al., 1991). However, the relation between
melatonin and bright light is not symmetrical (Fig. 1). The
measurement of endogenous melatonin in plasma, saliva or
urine is helpful in determining the circadian phase (Lewy et al.,
1999).
The wave form of human melatonin PRC is about 12-h phase-
shifted with respect to the PRC for bright light (Lewy et al.,
1998). In the melatonin PRC, the first half of the night reflects
the zone of reduced responses whereas in the PRC to light, the
phase shifting responses are reduced during the day. Intravenous
infusion of a physiological dose of melatonin has been found to
produce a melatonin PRC which is similar to pharmacological
PRC's (Zaidan et al., 1994).
Melatonin PRC's have been experimentally determined in
individuals with normal vision as well as in blind people (Arendt
et al., 1997; Lewy et al., 1998, 2004). In individuals with normal
eyesight who are entrained to the 24 h LD cycle, melatonin
administration in the afternoon and evening causes a phase
advance. By contrast, melatonin administration in the late night
or early morning causes a phase delay. Recently, a PRC was
constructed by administration of 0.5 mg of melatonin for 4
consecutive days to six subjects whose sleep schedules had not
been altered (Lewy et al., 2004).
The phase advance and phase delay zones of the melatonin
PRC are easily delineated in individuals with normal sight by
using DLMO as a marker of the circadian phase. By convention,
circadian time (CT) 0 is defined as the wake time in visually
normal individuals. An increase to 2 pg/ml of melatonin
(DLMO2) occurs at CT 13 while a 10 pg/ml plasma concentration
(DLMO10) occurs about 1 h later (at CT 14). The phase advance
zone for melatonin extends from CT 6 to CT 18 while the phase
delay zone extends from CT 18 to CT 6. This implies that the

Fig. 1. A schematic phase response curves (PRC) for light (dark line) and exogenous melatonin (dashed line) illustrate the direction, relative magnitude of the phase
shifts and phase relations. The phase shifts caused by light and melatonin are plotted against circadian times. Advance phase shifts are plotted in the upper panel and
delay shifts in the lower. The arrow represents the dim light melatonin onset (DLMO) and the rectangle represents duration of sleep. The filled triangle denotes the core
body temperature minimum. Reprinted with permission from Burgess et al. (2002).
 S.R. Pandi-Perumal et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 111
phase advance zone extends from 7 h before DLMO to 5 h after it
whereas the delay zone extends from 5 h after DLMO to 7 h before
it. Melatonin administration in the second half of the phase
advance zone produces the greatest phase advance (Lewy et al.,
1992; 2004; Middleton et al., 1997).
The phase shifting properties of melatonin are useful for the
entrainment of phase-disordered individuals such as those who
are totally blind. Administration of melatonin in the delay zone to
blind free running individuals showing circadian rhythms with
periods greater than 24 h compromised entrainment (Sack et al.,
2000). It is possible that initiation of melatonin treatment in the
PRC delay zone of blind free running individuals actually
changed melatonin PRC by changing melatonin receptor
sensitivity, thus compromising any eventual entrainment (Sack
et al., 2000). Lewy et al. (2004) recently showed that initiation of
melatonin treatment with a low dose (0.5 mg) in the delay zone of
PRC resulted in entrainment. This finding is in contrast to other
studies (Hack et al., 2003; Lockley et al., 2000) in which
initiation of a 0.5-mg melatonin treatment to blind people in the
delay zone failed to produce entrainment. In any event, it does
not appear that low-dose melatonin treatment should be initiated
exclusively at the advance zone of melatonin PRC to induce
eventual entrainment in blind people with free-running rhythms
(Lewy et al., 2004). This has a practical consequence: it is not
essential that circadian phase be ascertained before starting low-
dose melatonin treatment of blind people.
Sharkey and Eastman (2002) used the DLMO as a method
for measuring the effect of exogenous melatonin on circadian
phase changes in shift work simulation studies. The use of
DLMO for phase assessment indicated that the magnitude of the
desired phase advance was greater after administering higher
doses of melatonin. Subjects who took melatonin adapted to the
shifted sleep schedule faster than those who took placebo (56%
of subjects with a 0.5-mg dose, 73% of subjects with a 3.0-mg
dose) (Sharkey and Eastman, 2002).
Based upon the results of number of studies, a schematic PRC
to light has been constructed (Fig. 1). Construction of this PRC
included studies in which sleep time was held constant and a high
intensity of light was applied before and after sleep to study the
phase shifts (Burgess et al., 2002). In other studies, sleep schedule
was shifted (up to 12 h) and several pulses of light were applied at
various circadian phases to note the course of reentrainment
(Burgess et al., 2002). Light pulses were also applied to free
running (phase-disordered) individuals. The crossover point of the
human light PRC is based on the time of minimum of CBT
(CBTmin) that occurs at about the middle of sleep. Application of
light before CBTmin produces phase delays while light applied
after CBTmin produces phase advances (Jewett et al., 1994). Light
exposure close to the CBTmin has been shown to produce the
greatest shifts. The magnitude of the phase shift is shown to be
dependent on the intensity and duration of light with an increase in
magnitude occurring at higher intensities of light (Eastman, 1992).
Several reports on PRCs for light have been published de-
scribing the circadian clock responses to light. In a study in which
bright light was administered for 5 h on three consecutive days,
phase shifts as large as 12 h were observed after light was applied
around the CBTmin (type 0 PRC) (Czeisler et al., 1989; Duffy and
7
Wright, 2005). Contrary to other reports that had demonstrated
phase delays to single light pulses, Honma and Homna (1988)
reported a PRC without a significant phase delay region. A study by
Jewett et al. (1994) showed that in human subjects the early portion
of the phase delay region is poorly characterized, and that there is a
region of peak amplitude as well as a region of phase advance.
These findings support the view of the human circadian pacemaker
as being not simply a phase-only oscillator and that a full
description of human circadian resetting responses to light required
an analysis of both the phase and amplitude of phase shift data.
A more comprehensive PRC to single light pulses admin-
istered over the entire ranges of circadian phases was under-
taken by Khalsa et al. (2003). In that study, 21 healthy, entrained
subjects underwent pre - and post-stimulus constant routines in
dim light with maintained wakefulness in a semi-recumbent
posture. Phase advances (positive values) and delays (negative
values) of melatonin rhythm were plotted against the timing of
the centre of the light exposure relative to the melatonin mid-
point on the pre-stimulus constant routine. Phase delays were
generated when light pulses were delivered before the circadian
phase 0 h, and phase advances were generated when light pulses
were applied after circadian phase 0 h. Delivery of light pulses
close to the CBTmin normally produces large phase shifts of 12 h
in magnitude (type 0 PRC). However, phase shifts were near
zero when the light pulses were delivered close to the circadian
phase 0 (the so-called type I PRC) (Khalsa et al., 2003). Thus
human beings are capable of type I and type 0 resetting
depending upon the application of resetting stimulus (Jewett
et al., 1994). The peak to trough amplitude of the PRC in the
latter study was found to be 5 h and has been shown to be
consistent with other reports (Wirz-Justice et al., 2004). It is
important to note the relevance of light intensity for accurately
predicting the response of the human circadian pacemaker
(Khalsa et al., 2003; Zeitzer et al., 2000).
Based on studies of the effects of light on plasma melatonin
profiles in rodents, Illnerova and Vanecek (1985) hypothesized
that two coupled oscillators existed: an evening oscillator
associated with melatonin onset, and a morning oscillator
associated with melatonin offset. However, studies on the light-
induced phase shifts of melatonin onset and offset in humans are
controversial. Differences between the DLMO and other phase
markers do not necessarily mean that there are separate
oscillators inasmuch as relative sensitivity to noise and masking
effects could also account for the observed differences.
Results from some studies indicate that phase shifts in
melatonin onset are greater than phase shifts in melatonin offset
(Cagnacci et al., 1997; Deacon and Arendt, 1994; Hashimoto et
al., 1997; Honma et al., 1997; Parry et al., 1997; Van Cauter et al.,
1994) whereas other studies have reported opposite effects (Foret
et al., 1993; Lewy et al., 1985). Additionally, there have been
reports of the comparative effects of bright light or melatonin in
their capacity to phase-shift circadian rhythms. Studies by Lewy
et al. (1984) demonstrated that the maximal phase shift induced
by melatonin was approximately of 1 h whereas the maximum
phase shift induced by bright light was 12 h. Sleep phase shifted
as much as 12 h with bright light whereas no shift in sleep phase
was noted when melatonin was used as a phase resetting agent.
8 S.R. Pandi-Perumal et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 111
Mitchell et al. (1997), by applying high intensity bright light
to human subjects during the night shift (during phase advance
portion of light PRC), advanced the CBTmin by 74% of that
which would be required for a full effect. By comparing these
effects with a study of phase shifting (Sharkey et al., 2001,
Burgess et al. (2002) it was concluded that the phase shifting
effect of melatonin appears to be similar to that of high intensity
light. In the light exposure study (Eastman et al., 1995) the light
stimulation was administered for 8 nights whereas melatonin
was only given for 4 nights (Sharkey et al., 2001).
6. 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 suf-
fering 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
melatonin rhythm after 8 h advance of the sleep/wake cycle. A
3 h delay in sleep onset applied for 3 days was effective for
delaying significantly DLMO when compared to 3 days of sleep
at a normal time, or after advancing sleep onset for 3 h (Gordijn et
al., 1999; Gooneratne et al., 2003), Buxton and colleagues'
finding that total darkness too early in the afternoon (usually
accompanied by sleep) causes immediate phase shifts indicates
that these extreme conditions could be a potential confound for
using the DLMO as a phase marker (Buxton et al., 2000).
However, the shifts in DLMO were not accompanied by shifts in
body temperature or changes in latency to the first rapid eye
movement sleep episode. These findings therefore raise doubts
about the reliability of the DLMO as a marker of circadian phase
in the presence of sleep disturbances (Gordijn et al., 1999).
Indeed, DLMO can be readily estimated in people whose sleep
times are minimally affected by work, class and family
commitments but it remains to be established whether the
DLMO can be accurately estimated in people with greater work
and family responsibilities that affect their sleep times (Burgess
and Eastman, 2005). It must be noted, however, that DLMO has
proven useful for predicting melatonin efficacy in the treatment
of children with idiopathic chronic sleep onset insomnia (van der
Heijden et al., 2005).
A delayed melatonin onset presumably plays a key role in the
pathophysiology of delayed sleep phase syndrome (DSPS), one
of the most prevalent circadian rhythm sleep disorders seen in our
modern society. A number of studies have examined the efficacy
of exogenous melatonin in DSPS patients. Lewy et al. (1992)
found that melatonin administered 5 h before endogenous mela-
tonin onset advanced the circadian rhythms most. Extending these
results, Nagtegaal et al. (1998a) administered melatonin 5 h be-
fore melatonin onset and found effective in phase advancing the
sleep/wake cycle in DSPS. Hence the administration of melatonin
5 h in advance to DLMO is recommended as the precise time for
treating DSPS. In a recent study on 13 subjects with DSPS
(Mundey et al., 2005), melatonin (0.3 t0 3 mg) administered
between 1.5 to 6.5 h prior to DLMO for a 4 week period advanced
the circadian phase of endogenous melatonin and sleep in a phase-
dependent manner. The magnitude of the phase advance
correlated strongly with the time of melatonin administration.
Not only in adults but also in children the magnitude of the phase
advance in dim light melatonin onset correlates strongly with the
time of melatonin administration (Heijden et al., 2005).
Bright light administered during the phase advance part of the
PRC also advances the sleep wake rhythm. Since sleep/wake
rhythm (and also the 24 h temperature and cortisol rhythms) is
linked to the melatonin rhythm, appropriate administration of
melatonin and bright light can be very effective to shift the sleep/
wake rhythm.
7. 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). Circa-
dian 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 is used as a
non-invasive method for studying circadian rhythms in psychiatric
patients particularly those on medication. In a study of 12
medicated patients with rapidly cycling bipolar disorder, Leiben-
luft et al. (1996) found a mean time for DLMO of 22.01 1.86 h in
salivary samples and of 22.00 2.06 h in plasma samples.
Various studies have now demonstrated a close correspondence
between results obtained with plasma and saliva samples in
measurements of melatonin onset. Using DLMO as a marker,
Lewy et al. (1987) and Sack et al. (1990) demonstrated that
circadian rhythms are phase delayed in patients with seasonal
affective disorder (SAD) when compared to normal controls. Phase
delay of circadian rhythms in hypersomnolent SAD patients has
been confirmed by Dahl et al. (1993) using the DLMO as a phase
marker, SAD patients exhibiting a 92-min phase delay in DLMO
and a 146-min phase delay in CBT as compared to normal controls.
Daily exposure to bright light in the morning and the evening has
been found effective in treating patients with SAD (Rosenthal et al.,
1985). A number of studies have otherwise shown the advantage of
morning light over evening light in treating winter depression
(Golden et al., 2005; Mallikarjun and Oyebode, 2005; Sohn and
Lam, 2004). Using DLMO, Terman et al. (2001) demonstrated that
morning and evening light exposure at 10,000 lx, 30 min per day,
caused phase shifts of melatonin rhythms consistent with those
predicted from human PRC. A significant finding of those studies
was the correlation found between the magnitude of phase
advances of DLMO after morning light and the improvement in
depression rating. This was in agreement with earlier reports (Lewy
et al., 1987; Sack et al., 1990), which showed that improvement
after morning light was coincident with the phase advance of
DLMO. Based upon DLMO testing, Terman et al. (2001)
recommended that for maximum advantage, light therapy of
10,000 lx should be scheduled in a circadian rather than a clocktime
manner, i.e., about 8.5 h after baseline DLMO. In SAD patients, the
 S.R. Pandi-Perumal et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 111
DLMO/sleep interval may be an important marker for circadian
alignment or misalignment (Lewy et al., 2004) as well as the
temperature minimum/sleep offset interval (Burgess and Eastman,
2004). This contradicts somewhat with the suggestion that the more
a SAD patient is phase-advanced with morning light, the greater the
antidepressant response (Terman et al., 2001).
Investigations of melatonin profile provide indirect evidence
for the involvement of the SCN in the pathogenesis of SAD and
response to bright light treatment. Patients with SAD may
generate a biological signal of change in season that is absent in
healthy volunteers (Golden et al., 2005; Mallikarjun and
Oyebode, 2005; Sohn and Lam, 2004). In SAD patients, the
duration of the nocturnal period of active melatonin secretion was
longer in the winter than in the summer (as compared to no change
in normal volunteers). According to Wehr et al. (2001) these
abnormalities demonstrate that the pacemaker's signal of day
length is not a passive response to the LD cycle but reflects the
processes taking place in SCN cells. Duration of melatonin
secretion in constant dim light in SAD patients was modified
differently by changes in season as compared to healthy controls.
While a 38-min change in the duration of the circadian
pacemaker's day length signal between winter and summer
season might be considered small, a change of such a magnitude
in photoperiod length was sufficient to elicit behavioral changes
in experimental mammals (Wehr et al., 2001). However, it must
be noted that these findings were made primarily in men (who
represent a small fraction of SAD patients) and that this difference
occurred in the summer when compared to normal controls (when
SAD patients are euthymic). In any event, DLMO is useful for
evaluating patients with winter depression, and when used
comparatively during the summer and winter seasons may be
useful for elucidating the neural circuits that mediate the
pathogenesis of this condition.
8. 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 differ-
entiated, 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
chronobiological component of sleep or mood disorder. DLMO
can also provide guidance for the optimal timing of bright light
treatment or of melatonin administration. Recently, the DLMO
has been found useful for assessing effects of the length of day
during summer and winter months in patients suffering from
SAD. The evaluation of the DLMO and the extent to which it
deviates from established normative values has increasingly
proven to be a useful test for sleep disorders and for measuring
phase disruption in the psychiatric assessment of mood disorders.
A number of potential applications are envisioned for this
useful test. The research findings to date suggest that the DLMO
marker will make a significant impact on various lines of
scientific inquiry and in extending clinical understanding by: (a)
9
improving sensitivity and reliability of melatonin assays;
(b) extending its use to patients with rhythm perturbation in a
number of clinical settings; and (c) inasmuch as living organ-
isms are predictable resonating dynamic systems that require
different amounts of a drug at predictably different times with-
in the circadian cycle, assessment of phase position by DLMO
will help to maximize desired and minimize undesired drug
effects.
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