Chronobiology Inremarronnl. Vol. 6. No. 1. pp. 93-102, 1989 0742-0528/89 $3.00 t 0.

00
Printed in Great Britain Pergarnon Press plc
1989 International Society of Chronobiology

THE DIM LIGHT MELATONIN ONSET AS A MARKER FOR

CIRCADIAN PHASE POSITION
Alfred J. Lewy and Robert L. Sack
Sleep and Mood Disorders Laboratory, Departments of Psychiatry, Ophthalmology and Pharmacology,
The Oregon Health Sciences University, Portland, OR 97201, U.S.A.
(Received f o r publicarion July 1988)
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Abstract-Masking is known to affect a variety of circadian rhythms, making it difficult to use them as reliable
markers of circadian phase position. Melatonin may be unique in that it appears to be masked only by (bright)light.
Sleep and activity do not appear to influence the melatonin rhythm. By measuring the onset ofmelatonin production,
a clearly demarcated event, we can reliably assess circadian phase position, provided blood is sampled under dim
light (the dim light melatonin onset, or DLMO). Ihe DLMO has been useful in assessing the phase-shifting
properties of bright light and in phase typing patients with chronobiologic disorders, such as winter depression.

Key words-Melatonin, circadian rhythms, masking, winter depression, bright light.

Considerable interest has developed in the use of production) and the appearance of melatonin in
human plasma melatonin as a marker for the circulation.
circadian rhythms. Animal and human studies In mammals, production of melatonin occurs
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have shown that circulating levels of melatonin
are exclusively derived from the pineal gland (1).
Thus, measurement of its plasma levels is an
accurate assessment of pineal production of
melatonin in humans. In both diurnal and
nocturnal animals, the shape of the melatonin
secretory curve has certain similarities: pineal
production of melatonin occurs mostly at night.
This is unique, since [with the possible exception
of CSF vasopressin (2)] the phase relationship of
all other circadian rhythms is conserved with
respect to the activity-rest cycle and not the
light-dark cycle.
In most species, melatonin levels are low
during day, during which there is little secretion,
pulsatile or otherwise. Sometime after dusk,
melatonin levels abruptly rise (the melatonin
onset), following which, active secretion is
maintained until before dawn. Thus the shape of
this curve resembles a square wave more than a
sine wave. What may vary among species-and
perhaps among individuals-is the lag time
between when the pineal begins its nightly de
novo synthesis of mRNA and N-acetyltrans-
ferase (the rate-limiting step in melatonin
in response to sympathetic stimulation of the
pineal with the attendant release of norepine-
phrine from post-ganglionic neurons and the
action of this neurotransmitter on beta-l-adren-
ergic receptors located on the pinealocytes. The
source of this sympathetic stimulation is the
suprachiasmatic nucleus (SCN) of the hypothal-
amus, which then generates the circadian rhythm
of melatonin production and perhaps most, if
not all, other circadian rhythms as well. The
SCN, in turn, is synchronized to the light-dark
cycle through photic input transmitted by the
retinohypothalamic tract.
Like other circadian rhythms, the melatonin
rhythm free-runs under conditions of constant
darkness with a period slightly different from 24
hr. We have shown that most, if not all,
totally blind individuals who have been studied
free-run with intrinsic periods slightly greater
than 24 hr (3,4). Unlike other circadian rhythms,
the melatonin rhythm does not seem to be
directly affected by the activity-rest cycle or by
sleep, activity or stress [reviewed by Lewy (5)].
The shape of the melatonin curve is similar in
blind and sighted people. In blind individuals

Correspondence should be addressed to Dr A. J. Lewy, L469, Oregon Health Sciences University, Portland, OR 9720 1, U.S.A.
93
 94
there are the same active and basal phases of
about 12-hr duration as in sighted individuals;
active secretion stops after about 10 hr, even in
the complete absence of light perception. There-
fore, the light-dark cycle is not necessary to
either turn on or turn off melatonin production:
the rhythm is self-sustaining and endogenous.
Like other circadian rhythms, animal studies
have shown that the melatonin rhythm appears
to be regulated by the light-dark cycle in a way
that can be described by a phase response curve
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(PRC) (6). Unique to melatonin production,
light also has an acute suppressant effect:
exposure to light during the night immediately
and profoundly suppresses melatonin produc-
tion. Until recently, human chronobiologists
[reviewed by Czeisler (711 and pineal physio-
logists [reviewed by Lewy (8)] had come to the
conclusion that humans were relatively unaffec-
ted by light. For example, human melatonin
suppression was thought not to be suppressible
by light, despite the fact that other animal species
respond in this way to acute light exposure
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during the night.
This thinking changed dramatically following
our report in 1980 that human nighttime
melatonin production could be suppressed by
light, providing it was sufficiently bright (8).
Light of 2500 lux almost completely suppressed
melatonin production, whereas ordinary room
light (500 lux) was not very effective. Apparent-
ly, previous studies used insufficiently intense
light [reviewed by Lewy (8)]. This finding
suggested that humans had biological rhythms
that were cued to the natural (bright) light-dark
cycle, unperturbed by the use of ordinary-
intensity indoor light. This finding further
suggested that bright artificial light might be
used to experimentally, and perhaps thera-
peutically, manipulate biological rhythms in
humans.
In 1983, Wever (9) demonstrated that he was
able to increase the range of entrainment of
human activity-rest and temperature circadian
rhythms by using 4000 lux light; Eastman (10)
later confirmed this finding. Wever (9) pointed
out that the previous thinking that light was far
inferior to social cues was probably in error, due
to the use of insufficiently intense light. Wever
Chronobiology International
also pointed out that Czeislers demonstration
(7) of superior entraining effects of absolute
dark-light cycles was confounded by the behav-
ioral effects of total darkness. Czeisler (11)
agreed with this assessment, at least in so far as
the sleep-wake cycle was not held constant in his
earlier study (7): the effect of the light-dark cycle
was not separated from the effect of the
sleep-wake cycle. Czeisler (1 1) has also criticized
the Wever study (9) for the same reason. Both the
Czeisler and the Wever studies studied the
activity-rest and temperature rhythms, which are
vulnerable to masking influences.
In 1983 we reported successful treatment of
delayed sleep phase syndrome using bright light
scheduled in the morning (12). In 1984, we
published the first data showing phase-shifting
effects of light holding the sleep-wake cycle
constant (13, 14). Four normal volunteer sub-
jects slept between 2300-0600 for I5 days. For
the first day of study, the natural (bright) light-
dark cycle was such that dusk was between
1930 and 2100 and dawn was between 0600
and 0730. Then for 1 week subjects avoided
bright light (and sunlight) after 1600; thus, dusk
was advanced to 1600. For another week, dusk
was held at 1600 and dawn was delayed to 0900,
i.e. subjects avoided bright light (and sunlight)
between 1600-0900. The first day of advanced
dusk the onset of melatonin production ad-
vanced 1.5 hr. It remained at this phase position
for 1-2 days and advanced one more hour by the
end of the week, as did the offset. During the first
day of delayed dawn there was no change in the
melatonin rhythm. However, by the end of the
week there was a delay of 1 hr in both the onset
and the offset. These findings are the first data
demonstrating phase shifts of an endogenous
circadian rhythm following shifts of the bright
light-dark cycle (holding the sleep-wake cycle
constant), effects consistent with the common
features of PRCs described for most species.
We have also interpreted these findings as
consistent with the clock-gate model that we
have proposed to explain how the suppressant
and entrainment effects of light combine to
produce the shape of the melatonin secretory
curve (5). According to this model, in animals
whose intrinsic periods are > 24 hr, dawn should
 Dim Light Melatonin Onset
be relatively more important than dusk for
entrainment, and dusk should be relatively more
important than dawn for inelatonin suppression.
(The opposite should be true for animals whose
intrinsic periods are < 24 hr.) For humans,
whose active phase of melatonin production is
never > 10-12 hr in duration, the suppressant
effect of light should not occur in photoperiods
shorter than 12 hr in duration. The clock-gate
model and our data further suggest that bright
light can not only suppress active melatonin
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production once it has begun but also that bright
light can suppress the onset of melatonin
production. Consequently, when using mela-
tonin levels to mark circadian phase position,
not only should bright light be avoided through-
out the night but it should be avoided after 1700
or 1800 so as not to suppress the signal that
initiates melatonin production in the evening.
Melatonin levels can be used in a variety of
ways for determining circadian phase position.
Because of its square wave pattern, cosinor
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analysis is not appropriate. More appropriate
ways to determine phase position from the
melatonin pattern would be to use the onset,
peak or offset. Like a train of constant car-
length, any point of the curve is suitable for
determining phase position, assuming that the
duration of melatonin is constant (in dim light
conditions). The onset is preferable for several
reasons. Once nighttime melatonin production
begins, beta-adrenergic receptors in the pineal
become subsensitive (15). Furthermore, during
the course of the night, melatonin precursors can
become depleted. Both of these phenomena can
account for decreasing melatonin levels during
the night for reasons other than those related to
the timing of melatonin production. Of all of the
portions of the melatonin curve, the onset is
theoretically least affected by the development of
beta-adrenergic subsensitivity and melatonin
precursor depletion that might develop during
the night.
There is some disagreement over whether or
not one or two oscillators govern the onset and
offset of melatonin production. Illnerova (16)
has argued that her rodent light-pulse experi-
ments can be best explained by two oscillators,
one that is cued primarily to dusk which controls
95
the onset and one that is cued primarily to dawn
which controls the offset. While her data are
impressive and her logic is compelling, we
disagree with her main conclusion, particularly
as it might apply to humans.
First of all, melatonin production appears to
be regulated somewhat differently in primates
than in rodents [reviewed by Illnerova (16)]. In
rats, a 1-min pulse of light in the first half of the
night suppresses melatonin production for sev-
eral hours. In primates, melatonin production
resumes shortly after the light pulse ceases (8,
17). In rats, a 1-min light pulse in the second half
of the night stops melatonin production for the
remainder of the night, but this is not the case in
primates (8, 17). Therefore, it would not be
surprising if human melatonin production was
regulated by one oscillator, even if it were
established that rodent melatonin production
was regulated by two oscillators.
Indeed, Illnerova first proposed the two-
oscillator model to explain dynamics of suppres-
sion of melatonin production in the rat described
above (16). She originally stated that there need
not be a separate suppressant (as opposed to
entrainment) effect of light, hypothesizing that
the delay in the resumption of melatonin
production in the first half of the night was due to
an immediate phase delay in the onset oscillator
and that the cessation of melatonin in the second
half of the night was due to an immediate phase
advance in the offset oscillator to a time at or
before the light pulse (16).
On the other hand, our human data (described
above) suggest that there is a suppressant effect
of light that can be distinguished from an
entrainment effect. The immediate advance in
the onset the first night of advanced dusk
suggests removal of a suppressant effect of
evening light. (There was no immediate delay in
the onset or the offset on the first day of delayed
dawn to suggest removal of a suppressant effect
of light.) The changes in the onset and offset that
occurred with several days of advancing dusk and
delaying dawn, were most likely due to the
entrainment effect of light, given the expectation
of transients over the course of phase-resetting.
Animal data from naturalistic studies or
experiments in which photoperiod is mani-
 96
pulated are compatible with either a one-
oscillator or two-oscillator model. Depending on
ones assumptions, data from all experiments
performed to date can be explained by either a
two-oscillator model or a one-oscillator model
and a suppressant effect of light. Notably,
Illnerova has modified her one-oscillator model
to include a suppressant effect of light under
extremely long photoperiods; she has also
acknowledged that morning light appears to
predominate over evening light in entrainment of
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both oscillators (17).
We originally proposed the clock-gate model
to explain the seasonal onset-offset phase
paradox (5), which is that the onset and offset
manifest phase changes in opposite directions
throughout the year: the onset occurs later in the
summer than in the winter, while the offset
occurs earlier in the summer than in the winter.
This, of course, results in the changing duration
of melatonin production during the year which is
important in the timing of many seasonal
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rhythms in animals. The question arises, how-
ever, that opposite changes in phase cannot
easily be accommodated by one pacemaker. We
have explained this paradox by proposing the
clock-gate model (5): the apparently later onset
of melatonin production in the summer in
animals whose intrinsic periods are > 24 hr is the
result of the gating effect of a photoperiod
> 12 hr. Alternatively, Illnerovas two-oscillator
model can also explain this paradox (16).
Perhaps there are two oscillators and a suppres-
sant effect of light. Resolution of these questions
will probably not occur until direct observation
of the underlying oscillators can be accom-
plished.
If there is more than one oscillator for
melatonin production, we may only be able to
assume that the melatonin onset is marking the
phase of the evening oscillator. Nonetheless,
these oscillators seem to be tightly coupled. It
also makes sense to study the melatonin rhythm
under dim light conditions, if only to eliminate
the masking effects of the natural photoperiod.
In other words, to use melatonin levels as a
marker for circadian phase position, blood
should be drawn under dim light conditions after
1700-1800. T o use melatonin levels as a marker
Chronobiology International
for seasonal changes in the pattern that varies
according to the photoperiod, blood should be
drawn under naturalistic conditions.
In humans, there are no melatonin data that
cannot be explained by a one-oscillator model.
There is another one (18) versus two (19, 20)
pacemaker controversy, however. This contro-
versy, different from the one described above for
the melatonin onset and offset, is over whether or
not there are two endogenous pacemakers for
human circadian rhythms, the activity-rest cycle
having a separate endogenous pacemaker from
the other endogenous circadian rhythms, such as
temperature and melatonin. In our opinion,
there may be untold numbers of oscillators,
perhaps a hierarchical system of oscillators for
each overt circadian rhythm, which are driven by
slave oscillators entrained to environmental time
cues by one or more endogenous circadian
pacemakers. Endogenous pacemakers, unlike
slave oscillators, must necessarily be responsive
to an environmental zeitgeber as described by a
phase response curve in order to accomplish
phase control as well as entrainment.
Our human studies of melatonin suggest that
there is only one zeitgeber-light-for which
evidence for a phase response curve has been
demonstrated. In addition to Wevers demon-
stration (9) of bright lights ability to increase the
range of entrainment of the activity-rest and
temperature rhythms [followed by Eastman
(lo)], we and others have shown phase-shifting
effects of light holding the sleep-wake cycle
constant (4, 5 , 11, 21). Furthermore, more
classical phase response curves are preliminarily
being demonstrated by Honma (22). A phase
response curve in humans has not yet been
demonstrated for any other zeitgeber. This
suggests that there is only one zeitgeber and only
one endogenous pacemaker. Indeed, Czeisler
(one of the main proponents of the two-
pacemaker model) has recently (1 1) retracted his
and Kronauers model (20) in which the
temperature (melatonin) pacemaker was en-
trained to environmental zeitgebers mainly
through the activity-rest pacemaker.
We have suggested ( 5 ) that the apparent
entrainment of the human temperature rhythm
by sleep is an indirect effect, by which sleep (with
 Dim Light Melatonin Onset 97
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Figure 1. Sleep and melatonin rhythms in a totally blind subject. Living at home, this
subject had a I-day laboratory determination of his free-running melatonin onset (m)
carried out every few weeks for several months. The data are plotted on a repeating
time scale. Sleep times were more or less entrained to social cues (dark bars). The
melatonin onsets fall reliably ( r = 0.99, P = 0.001) on the fitted regression line n o
matter when they occur in relation to sleep time, suggesting that sleep does not affect
the melatonin circadian rhythm.

the closing of the eyes) imposes its structure upon When using melatonin as a marker for
the (bright) light-dark cycle: the closed loop circadian phase position, we recommend the
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hypothesis. Sleep may be the one circadian
rhythm that is directly affected by social cues. It
appears to be more loosely coupled to the
pacemaker than the other circadian rhythms that
are not susceptible to social and psychological
influences.
Further evidence that there is not a separate
endogenous pacemaker for the activity-rest
cycle comes from studies of blind people. The
free-running melatonin rhythm of totally blind
individuals (Figure 1) does not appear to be
influenced by social cues or sleep, as it continues
its inexorable free-run, cycle after cycle (Sack
and Lewy, in preparation). This is further
evidence for a single pacemaker that drives all
circadian rhythms.
As mentioned above, melatonin appears to be
less influenced by direct masking effects due to
sleep and wakefulness, compared to other
circadian phase markers, such as temperature or
cortisol. We have measured cortisol in some of
the same totally blind subjects in whom mela-
tonin was measured (Sack and Lewy, in prepar-
ation). It is clear that sleep and wakefulness have
a profound affect on cortisol levels (Figure 2)
and makes it less desirable than melatonin as a
phase marker.
melatonin onset. As mentioned above, it is as
good or better than any other part of the
melatonin secretory curve for this particular use.
Furthermore, the melatonin onset is advan-
tageous for several other reasons. Subjects can be
studied in the evening as outpatients. Sleep is not
disturbed. Blood drawing is minimized. High
resolution at frequent sampling intervals can be
conveniently obtained.
There is only one potential known masking
effect on melatonin: bright light. However, we do
not know to what extent dim light might also be
capable of causing masking (23, 24). For that
matter, we do not know the threshold of intensity
for light to have entraining effects. Conse-
quently, we recommend that melatonin samples
be obtained under the dimmest possible light.
For the onset, dim light conditions should begin
no later than 12 hr before dawn (usually we begin
dim light conditions between 1700-1800). We
call this the dim light melatonin onset, or
DLMO.
The DLMO appears to be a useful marker for
circadian phase position. Comparing normals to
patients has revealed some potential differences
in the PRC that might not have been previously
appreciated without this comparison. The bright
 98
10
10
0
0 winter of 1980, when we successfully treated a
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I rhythms depend to some extent on the circadian
\ timing system.) Winter depressive patients, as
HoLr (milllary time)
Figure 2. Free-running melatonin and cortisol rhythms in a
totally blind subject. A totally blind subject was studied for
24 hr on three different occasions. The data are double-
plotted. The three dates of hormonal determinations were
12/6/86, 12/19/86 and 1/2/87 (top to bottom). A line was
fitted to the melatonin onsets (time when melatonin levels
reached 10 pg/ml). n7e melatonin circadian rhythm (as
indicated by the melatonin 0nset)appears to provide a clearer
estimate of circadian phase position compared to the cortisol
circadian rhythm.
Chronobiology International
light suppression of melatonin finding suggested
that humans might have biological rhythms that
respond to the natural (bright) light-dark cycle
unperturbed by the use of ordinary-intensity
room light and that bright artificial light might
be used experimentally, and perhaps thera-
peutically, to manipulate these rhythms. Our
first test of these implications occurred in the
patient (with a recurrent winter depression which
spontaneously remitted each year in the spring)
by exposing him to 2000 lux light between 0600
and 0900 and between 1600 and 1900 (25). After
4 days of this bright light exposure schedule, he
began to switch out of his depression, 2 months
before this was due to happen spontaneously.
Since then, hundreds of other such winter
depressive patients have been similarly studied
[we have reviewed the antidepressant effects of
bright light elsewhere (26)]. Dim light, an
appropriate placebo control treatment, has been
shown to be significantly less antidepressant (27,
28).
Since then, we have been interested in the
phase-shifting effects of light and whether or not
winter depressive patients might have a circadian
rhythm disorder, rather than a disorder involv-
ing seasonal rhythms. (Of course, seasonal
opposed to melancholic major depressives who
often have early morning awakening, have
difficulty getting up in the morning. Conse-
quently, whereas the melanchoIic depressed
patients had been previously hypothesized to be
phase advanced, we thought that winter depres-
sive patients were phase delayed.
We have found that these patients preferen-
tially respond to morning light compared to
evening light (21). In our first study(21), we also
found that patients had significantly later
DLMOs than normal controls, even after a week
of standardized sleep-wake and light-dark
conditions. Subsequently, we found that the
decline in depression ratings correlated with the
advance in the melatonin onset. We were also
able to measure the amount of phase shifts after
2 hr of morning light and after 2 hr of evening
light. If we had not studied these phase-delayed
 Dim Light Melatonin Onset
patients, we might not have demonstrated a
statistically significant phase advance after
morning light scheduled between 0600 and 0800.
This is because controls did not significantly
advance; only the patients did.
In a subsequent study (Lewy et al., in
preparation), we compared 0.5 and 2 hr of
morning light. Two hours of morning light
caused more of a phase advance than did 0.5 hr
(PGO.01). In this study, we found a good
correlation ( r = 0.95) between the decline in
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depression ratings and the advance in the DLMO
(29). In a third study comparing morning versus
evening light (Sack and Lewy, in preparation),
we scheduled evening light 1 hr earlier than in
our first morning versus evening light study and
found similar results. These studies are all
compatible with a phase response curve showing
relatively less phase shifts during the middle of
the day.
There was a trend for onsets to be delayed in
this study a t baseline, which was significant when
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combined with the first morning versus evening
light study but was not significant when the 0.5
versus 2 hr study was included in this pooling of
the data. In the first study and in a replication
study, we found that patients advanced more in
response to morning light and delayed less in
response to evening light than did normal
controls. This finding led us to propose the A-D
6 4 2 0 2 4
Time beiwccn GLMO and onsel of PM lighl (hours)
Figure 3. Baseline DLMO predicts the delay response to
evening light. Melatonin onsets are determined in both
normal controls (0)and winter depressive patients (m) aftera
week of baseline conditions and after a week of evening
bright light (1900 to 2100 or 2000 to 2200). The fitted
regression line showed a statistically significant (P<0.001)
correlation (r = 0.86), indicating that the later the baseline
melatonin onset, the less the phase delay response to evening
light. This finding is consistent with the hypothesis that the
melatonin onset is marking the phase position of its phase
response curve.
99
differential, which is the advance response in the
DLMO relative to the baseline DLMO minus the
delay response relative to baseline. Theoreti-
cally, the greater the A-D differential, either the
more delayed is the PRC or the greater is the area
under the advance portion compared to the delay
portion, both of which possibilities are consistent
with phase-delayed circadian rhythms due to a
relatively longer intrinsic period.
The melatonin onset seems to be marking the
phase of its PRC. The phase delay response to
evening light is related to the baseline phase
position of the melatonin onset: the later the
melatonin onset, the less the phase delay effect of
evening light (Figure 3). The phase advance
response to morning light is also related to the
baseline phase position of the melatonin onset:
the later the melatonin onset, the greater the
phase advance response to morning light (Figure
4). Furthermore, the later the melatonin onset,
the greater the A-D differential (Figure 5 ) . These
data suggest that the melatonin onset is marking
the phase of its PRC.
Although the A-D differential correlates very
well with the baseline DLMO, the A-D differen-
tial may be a more reliable method of phase
typing because it takes into account inter-
individual differences in melatonin physiology,
such as in the biochemical lag time between the
onset of sympathetic stimulation of the pineal
and the appearance of melatonin in the circula-
tion, assuming of course that the intraindividual
r
D i m
3 -
.
.
5 5 2 -
2 2 -
L
0-
3 s -
a d 1-
2-
0
3 1 . , . , . , . , , , . . - ,
17 18 19 20 21 22 23 24
Ba5~111nc
mr?Istoriin o n i e l lime (hour of day)
Figure 4. Baseline DLMO predicts the advance response to
rnornin light. Melatonin onsets are determined in both
normafcontrols (0)and winter depressive patients (m) after a
week of baseline conditions and after a week of morning
bright light (0600to 0800).The fitted regression line showed a
statistically significant (P < 0,001) correlation (r = 0.78),
indicating that the later baseline melatonin onset,,the greater
the phase advance response to morning light. This finding I S
consistent with the hypothesis that the melatonin onset is
marking the phase position of its phase response curve.
 100 C h r o n o b i o l o g y International

$ 6 - sponses to light will become a useful marker for

n .
-
1 $ 4 - circadian phase position, for phase typing and
g
5c :
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2:
:
for monitoring phase-shifting effects of light.
1 *1
This may be important, because of the masking
8 p 2- effects of sleep, wakefulness and stress on other
;
m g
? 4: - phase markers, such as temperature and cortisol.
9 6: The melatonin onset may also be useful
0 .
, , , , . , , , , , , , , , because of the controversy that surrounds the
17 18 19 20 21
22
Baseline melatoninonset lime (haw 01 day)
23 24 constant routine. Originally proposed by Mills
and co-workers (31) and then promulgated by
Figure 5. Baseline DLMO predicts the A-D differential. Czeisler and co-workers (32)9 the constant
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Melatonin onsets are determined in both normal controls (0)

and winter depressive patients )(. after a week of baseline
routine has been thought - by- some to eliminate
masking effects due to the sleepwake cycle. This
conditions, after a week of morning bright light and after a
week of evening bright light (see Figures 3 and 4). The A-D is not clear, since deprivation has been
differential is the advance response-to morning light minus reported by some of the same investigators to
the delay response to evening light. The fitted regression line phask shifts. ~ ~this procedure
~
showed a statistically significant ( P < 0.001) correlation
( r = 0.86). indicating that the later the baseline melatonin is cumbersome and may be associated with Some
onset, the greater -the A-D differential. This finding is stress. If the constant routine proves not to be
consistent with the hypothesis that the melatonin onset is
marking the phase position of its phase response curve. optimal for eliminating masking effects in the
estimation of circadian phase position, the
attractiveness of the DLMO increases. However,
variation in the lag time is small, which is a accurate and sensitive assays will be needed to
For personal use only.

reasonable assumption. Perhaps this is why use melatonin as a phase marker, particularly the
comparing patients to controls, the A-D differ- DLMO. DLMOs using salivary levels of mela-
ential yields a more significant difference tonin (which are about one-third those of
( P < 0.001) than the baseline DLMO ( P < 0.01). plasma) may have great applicability in the study
Furthermore, our one evening light responder of circadian rhythms at home, when travelling
had the most negative A-D differential of that and in the work-place. However, very sensitive
group of patients, but did not have the most assays, such as thegas chromatography-negative
phase advanced baseline DLMO. chemical ionization mass spectrometric assay
It is possible that a circadian rhythm in light (33), will be needed to determine daytime
sensitivity exists (30), but it is unlikely that a melatonin levels in saliva. Less sensitive assays
1-2 hr phase shift in this rhythm would signifi- (34) may have to use the entire nighttime
cantly increase interindividual variability in secretory curve to determine circadian phase
these phase shift responses. The A-D differential position or perhaps use some other (perhaps less
is also theoretically superior to the advance precise) technique to determine the melatonin
response to morning light alone [which also can onset, such as the half-maximum, which will also
reliably distinguish patients from controls require blood sampling during the middle of the
(PG O.OOl)] or to the delay response to evening night.
light alone, because the A-D differential takes In conclusion, measurement of plasma mela-
into account interindividual differences in light tonin levels appears to provide useful informa-
sensitivity per se. However, should it be shown tion about circadian phase position. The DLMO,
that there is no difference between certain patient which is obtained under dim light conditions,
populations and normals in light sensitivity (as appears to be free of significant masking effects,
assessed, for example, by the nighttime mela- has many advantages as a research tool and
tonin suppression test), then the morning light appears to be clinically useful as well. Our studies
advance response might be used as a simpler way of the baseline DLMO and its phase shift
to distinguish patients from normals. responses to morning arid to evening light have
Hopefully, the melatonin onset or its re- provided important data concerning the human
 Dim Light Melatonin Onset 101

circadian pacemaker, chronobiologic disorders
and bright light therapy.
Acknowledgements-The authors thank G. Clark, M. Mc
Reynolds, M. Blood, D. Jennings, J. Peterson and C.
Simonton for their help. Supported by PHS grants
CRR00334, MH43016 (R.L.S.), MH00703 (A.J.L.) and
MH40161 (A.J.L.).

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