Treating Chronobiologic Sleep and Mood Disorders with
by Alfred J. Lewy, MD, PhD
Treatment of mood disorders
with bright light is one of the more promising nonpharmacological
treatments of psychiatric disorders. The study of circadian rhythms and
their effects on biological functions and mood have provided fascinating
insights into the understanding of mental illness.
The study of circadian
rhythms involves measuring the temporal relationships between bodily
functions. Bodily functions frequently follow daily cycles with high and
low points which are useful markers in identifying the timing of
rhythms. It is then possible to compare relative phases of different
rhythms to determine whether a peak or crest of the curve has occurred
earlier (phase advanced) or later (phase delayed) than other conditions.
For example, a body temperature minimum that occurs at 4
is phase delayed (ie, occurs later) with respect to a body temperature
minimum occurring at 2 AM.
Conversely, the 2 AM minimum is
phase advanced (ie, occurs earlier) with respect to the 4
minimum. In other words, a phase advanced rhythm is one that is shifted to
an earlier time and a phase delayed rhythm is one that is shifted to a
The period of
rhythm refers to how often it repeats. Circadian rhythms recur
approximately every 24 hours. These rhythms recur precisely every 24
hours in the presence of 24-hour environmental time cues (zeitgebers),
particularly the 24-hour light-dark cycle. Under zeitgeber-free
conditions, human circadian rhythms free-run with an average period of
approximately 25 hours.1 Studies have shown
that the period of the melatonin production circadian rhythm in some
blind people is approximately 25 hours.2
BRIGHT LIGHT SETS HUMAN CIRCADIAN RHYTHMS
Until recently, chrono-biologists
agreed that social cues were the main zeitgebers for human circadian
rhythms and that the light-dark cycle, which is the most important
zeitgeber for animals, was relatively unimportant for humans.1
This view changed radically, however, after the discovery that exposure to
bright light suppresses nighttime melatonin production, whereas
ordinary room light is not sufficiently intense to be effective.3
One implication of these findings was that exposure to sunlight, which is
generally 20 to 200 times as bright as indoor light, could synchronize
human biological rhythms that remain unaffected by indoor light. A
second implication was that bright artificial light could be used
experimentally, and perhaps therapeutically, to manipulate biological
rhythms in humans.
Studies conducted by
and Czeisler6 have confirmed that bright
light is a potent zeitgeber for human circadian rhythms. Czeisler and
colleagues6 have recently modified their
mathematical model based on the results of these studies and now support
the single oscillator model proposed by Daan et al7
and Eastman8. This model presents a single
oscillator entrained directly and primarily by light. In other words,
most scientists agree that one master clock probably drives all
TREATMENT OF DEPRESSION WITH BRIGHT LIGHT
Our own work has
proceeded along both basic and clinical lines. In 1980, we treated our
first patient with bright light9. This
patient had a 13-year history of winter depression that remitted
spontaneously in the spring. Our first approach was to lengthen the
winter days by exposure to bright light between 6 and 9 AM
and between 4 and 7 PM. (Animals are
aware of day length by the interval between the light pulses at dawn and
dusk; light exposure during the middle of the day is relatively
unimportant for cueing biological rhythms.) Following the first
successful treatment, nine patients were treated the next year with
bright light and dim light exposure at these times10.
Lengthening the day with bright light was an effective antidepressant;
dim light had no effect.
HUMAN CIRCADIAN RHYTHMS AND USE OF MELATONIN
We next became interested
in how bright light might affect human circadian rhythms. Our work is
based on the hypothesis that humans have a phase response curve (PRC)
similar to those described for other animals11.
PRCs are empirically derived from experiments in which animals free-run
in constant dark and are briefly exposed to light pulses12-15.
Depending on when the light pulse occurs, they shift their rhythms
either in the advance direction (to an earlier time) or in the delay
direction (to a later time). If the pulse of light occurs during
subjective day (in constant darkness, subjective day is the activity
phase of diurnal animals and the rest phase of nocturnal animals), there
is a relatively small shift in rhythm. During subjective day, there is a
"dead zone" when light barely produces any shift at all. It is during
subjective night that light pulses produce the greatest phase shifts.
The closer to the middle of subjective night, the greater the magnitude
of the phase shift. Phase delay shifts occur in the first part of
subjective night; phase advance shifts occur in the second part of
subjective night. In the middle of the night, there is an inflection
point where only a few minutes separate a delay shift from an advance
shift. In practice, this means that bright light exposure in the morning
should advance circadian rhythms (shift them to an earlier time) and
that bright light exposure in the evening should delay circadian rhythms
(shift them to a later time).
We first tested our
hypothetical PRC by studying four normal volunteers in the summer who
slept between 11 PM and 6
We measured their plasma melatonin levels the first day and then advanced
dusk from about 9 PM to 4
PM by having them avoid bright light after
this time. After a week of advanced dusk, we delayed dawn from about 6
AM to 9 AM
by the same method for one week. After the first night of advanced dusk,
the onset of melatonin production shifted to one hour earlier.
Production remained stable for at least one more day. By the end of the
week, onset of melatonin production advanced by another hour as did the
offset. We interpret the end-of-the-week advance in both the onset and
the offset of melatonin production as a result of removing illumination
from the evening phase delay portion of our hypothesized PRC. However,
the advance in the offset the first night of advanced dusk was probably
due to removing a suppressant effect of light on melatonin production.
(Phase shifting effects are usually produced over a few days, whereas
the suppressant effect of light is an immediate one.)
Delaying dawn to 9
AM the second week caused a delay of about
one hour in both the onset and the offset of melatonin production. There
were no changes the first day. These data are consistent with the effect
of removing illumination from the morning phase advance portion of our
When sampling blood for
melatonin onset, subjects should be kept away from bright light in the
evening to avoid the suppressant effect of light on melatonin
production. Thus, if subjects avoid bright light after 5 or 6
PM, nighttime melatonin onset may be an ideal
marker for the phase shifting effects of light. The dim light melatonin
onset (DLMO) has a number of advantages as a marker for circadian
rhythms. First, it is the part of the melatonin curve that is least
influenced by biochemical and physiological variables that might affect
the amplitude of melatonin production. Second, subjects can leave after
11 PM. Third, sleep is not
interrupted. Fourth, blood volume is conserved.
We have also demonstrated
shifts in the melatonin rhythm as a result of adding bright light in the
morning or evening.18-19
We have found that, as predicted, bright light exposure in the evening
delays circadian rhythms and bright light exposure in the morning
advances circadian rhythms.18-20
DIAGNOSING ADVANCED OR DELAYED CIRCADIAN RHYTHMS IN
In applying these
findings to the clinical evaluation and treatment of patients with
suspected chronobiologic sleep or mood disorders, we propose that such
patients be "phase typed" into either the phase advanced or the phase
delayed type.18 If a patient's sleep or
mood disorder has a chronobiologic component that will respond to bright
light therapy, the patient should respond to either bright light in the
morning or bright light in the evening, depending on the phase type.
Patients with phase advanced circadian rhythms should respond to evening
light, which provides a corrective phase delay. Patients with phase
delayed circadian rhythms should respond to morning light, which
provides a corrective phase advance.
researchers hypothesized only a phase advanced type of chronobiologic
disorder.21-22 In the
phase advance hypothesis of affective disorders, circadian rhythms were
thought to be abnormally advanced with respect to real time and to
sleep. Advancing sleep in these patients,21
as well as sleep deprivation in the second (but not first) half of the
was a least transiently helpful in some cases. Consequently, an internal
phase angle disturbance was hypothesized, in which sleep was not as
phase advanced as the other circadian rhythms. We have expanded upon
this theory by describing a subgroup of depressed patients with phase
delayed circadian rhythms.18,19
We propose that these patients may have an internal phase angle
disturbance, in which sleep is not as delayed as the other circadian
SLEEP AS A MARKER FOR DIAGNOSING ADVANCED OR DELAYED
The most accessible, and
therefore clinically useful, marker for circadian phase type may be
sleep (sleep offset is more reliable than sleep onset). Paradoxically,
however, the cause of depression may be due to sleep not being as phase
shifted as other circadian rhythms. Sleep is shifted in the same
direction as the other circadian rhythms but not shifted sufficiently to
correct the phase angle disturbance. Furthermore, a shift in sleep
superimposes its structure upon the light-dark cycle which, in turn,
perpetuates an even greater shift in the other circadian rhythms.
Previous studies on advancing sleep in depressed patients and delaying
sleep in patients with delayed sleep phase syndrome did not specifically
take into account the resulting effect on the perceived light-dark
Delayed sleep phase
syndrome, characterized by an inability to fall asleep at a reasonable
time, has been treated by chronotherapy (successively delaying sleep 1
to 2 hours per day for several days until the desired bedtime is
Sleep is delayed because these patients are unable to advance their sleep
schedules. However, we have been able to help these patients fall asleep
several hours earlier by exposing them to bright light in the morning
(immediately upon awakening).11
TREATMENT OF ADVANCED OR DELAYED SLEEP SYNDROME
We have also successfully
treated patients with advanced sleep phase syndrome, characterized by
early evening fatigue and early morning awakening, by exposing them to
bright light in the evening.25 Sleep
disorders may not have an internal phase angle disturbance because in
these disorders all circadian rhythms, including sleep, may be phase
shifted to the same extent.
Patients with advanced
and delayed sleep phase syndrome must cooperate with these schedules and
must therefore be motivated to change. However, they can be reassured
that bright light exposure will help them to initiate and maintain the
phase shift. One problem with chronotherapy is that patients frequently
relapse. Chronotherapy is also unwieldy. Consequently, bright light
exposure will probably become the treatment of choice for patients with
advanced and delayed sleep phase syndrome.
OTHER VARIABLES AFFECTING TREATMENT RESPONSE TO LIGHT
In addition to phase
typing, we propose that there are three critical parameters for light to
be chronobiologically active in humans; intensity, wavelength, and
In a study done a few years ago, we showed that the optimum wave lengths
for melatonin suppression are around 509nm.27
This wavelength is representative of most white light sources.
Timing is still a
somewhat controversial issue, at least with regard to the treatment of
winter depression (or seasonal affective disorder, as it is sometimes
called). The Bethesda group has stated that the timing of bright light
is not critical, only its intensity and duration.28-30
They call this the photon counting hypothesis because only the number of
photons is important. They arrived at this hypothesis after testing and
then rejecting their melatonin suppression hypothesis for seasonal
affective disorder.31 Their thinking was
based on studies that suggested that lengthening the photoperiod at both
ends was not critical30 and that evening
bright light was effective in treating this disorder.28,29,32
Although there is general
agreement that lengthening the photoperiod at both ends is not critical,
we disagree with the Bethesda group when they discount the importance of
timing. First, photoperiod length is not the only aspect of timing; its
effect on shifting the phase of circadian rhythms is also important.
Second, many of the Bethesda group's studies were either not properly
controlled or were in some other way methodologically suboptimal.31
In brief, any study intended to demonstrate a mechanism of action should:
ˇ optimize the antidepressant efficacy of light treatment,
ˇ control sleep time and bright light exposure around dawn and dusk, and
ˇ take into account the phase shift hypothesis.
With regard to this latter point, bright light in the late morning or
early afternoon might cause some amount of phase advance, since we do
not know the precise boundaries of the "dead zone" of the PRC, either in
normal controls or patients.
TREATMENT OF SEASONAL AFFECTIVE DISORDER (WINTER
Most of our thinking
regarding the phase shift hypothesis has been the result of work with
winter depressive patients. Preliminary data collected in 1981 to 1983
suggested that these patients were phase delayed and would respond
preferentially to morning bright light exposure.16
During the winter of 1984-1985 we studied 14 winter depressed patients
(eight as outpatients and six as inpatients) and seven normal controls
at home.18,19 Throughout
the study subjects were not permitted to sleep between 6
and 10 PM. They remained indoors
shielded from bright light exposure between 5 PM
and 8 AM (The inpatients were also
exposed to bright light between 8 and 8:15 AM
and between 4:45 and 5 PM.). The
first week served to establish a baseline. The second week half of the
subjects were randomly assigned to either bright light exposure in the
morning (6 to 8 AM) or in the
evening (8 to 10 PM). The third
week their exposure time was changed to the other lighting condition.
The outpatients and the volunteers were studied for a fourth week during
which they were exposed to bright light both in the morning and in the
preferentially responded to morning light. Hamilton depression ratings
were significantly lower at the end of the week of morning light
compared with the baseline week or the week of evening light. Ratings
for the week of morning plus evening light were intermediate between
those at the end of the week of morning or evening light alone. It is
difficult to find any explanation for these results other than that the
light is phase advancing the circadian rhythms of these patients. This
would explain not only why the morning light was more effective than the
evening light, but also why the combination had an intermediate effect:
evening light, which would be expected to cause a phase delay in
circadian rhythms, could be counteracting the phase advance induced by
the morning light.
We were further convinced
of this phase shift explanation after examining the circadian rhythms of
our subjects. As a marker for circadian phase position, we used the dim
light melatonin onset (DLMO). Many other circadian rhythm markers, such
as temperature and cortisol, are affected by locomotor activity and
sleep. Melatonin production does not appear to be affected by acute
changes in locomotor activity or sleep.
Compared with the normal
controls, the DLMOs of the patients were significantly delayed at the
end of the baseline week. This may represent an abnormality in the
circadian system of the patients, ie, abnormally phase delayed circadian
rhythms. Morning light, which caused a remission, was associated with a
normalization of the DLMO. The combination of morning plus evening light
caused the patients' DLMOs to shift to intermediate phase positions, as
if the morning and evening light when given together were counteracting
During the winter of
1985-1986, we asked the following question: how much morning light is
needed to treat patients with seasonal affective disorder?33
Patients were exposed to bright light upon awakening between 6 and 6:30
AM and were crossed over to exposure
between 6 and 8 AM with withdrawal
weeks in between (to enhance the double-blind nature of the study, half
of the patients started on a baseline week and half were started on
light exposures). On average, the two light exposures had the same
antidepressant effect. However, there appeared to be subgroups. One
fourth of the patients appeared to respond better to two hours of bright
light exposure and one fourth of the patients appeared to respond better
to the one half hour exposure. We hypothesized that for the latter group
two hours of morning light caused too much of a phase advance. In both
our studies described here, patients' DLMOs advanced more than did those
of normal controls in response to morning light exposure, suggesting
that the PRCs of the patients are more delayed than are those of the
In the final week of the
1985-1986 study, we tested the same morning light exposure used during
the first or second week. When given during the last week of the study,
a particular light exposure had a much more antidepressant effect than
when given during the first week. We anticipated that the antidepressant
response to morning light might take longer than a week because the
patients had to advance their sleep to accommodate the morning light
exposure and thus retard closure of the phase angle between sleep and
the other circadian rhythms. To test this idea further, we found that
while holding the circadian rhythms of three winter depressive patients
constant with late-morning light, delaying their sleep caused a
remission in their depressive symptoms.33
Therefore, winter depression appears to be the result of circadian
rhythms that are phase delayed with respect to sleep. These
patients respond either to advancing their circadian rhythms (holding
their sleep time constant) or delaying their sleep (holding their
circadian rhythms constant).
for the practical treatment of patients with seasonal affective disorder
are provided in the
We hope that these
guidelines will be useful to the clinician in evaluating putative
chronobiologic sleep and mood disorders and in testing the effects of
appropriately timed bright light exposure. More research is necessary,
particularly in the identification of useful circadian phase markers
that might help to phase type patients. Either baseline time of the
melatonin onset or its phase shift response to morning and to evening
light may be useful for phase typing and for evaluating the phase
shifting effects of light. It seems probable that appropriately timed
bright light exposure will have important treatment applications for
chronobiologic sleep and mood disorders and may also be used to help
people with problems adjusting to shift work and air travel.34
Treatment Guidelines for Patients with Seasonal Affective Disorder
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