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Circadian Time of Morning Light Administration and Therapeutic Response in Winter Depression
Jiuan Su Terman, PhD;
Michael Terman, PhD;
Ee-Sing Lo, PhD;
Thomas B. Cooper, MA
Arch Gen Psychiatry. 2001;58:69-75.
ABSTRACT
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Background We investigated a possible mechanism of action for the antidepressant
response to light—phase advances of the circadian clock—by measuring
the onset of melatonin secretion before and after light treatment in the morning
or evening.
Methods Plasma melatonin was sampled in 42 patients with seasonal affective
disorder, in the evening or overnight while depressed and after 10 to 14 days
of light therapy (10 000 lux for 30 minutes) when symptoms were reassessed.
Results Morning light produced phase advances of the melatonin rhythm, while
evening light produced delays, the magnitude depending on the interval between
melatonin onset and light exposure, or circadian time (morning, 7.5 to 11
hours; evening, 1.5 to 3 hours). Delays were larger the later the evening
light (r = 0.40), while advances were larger the
earlier the morning light (r = 0.50). Although depression
ratings were similar with light at either time of day, response to morning
light increased with the size of phase advances up to 2.7 hours (r = 0.44) regardless of baseline phase position, while there was no
such correlation for evening light. In an expanded sample (N = 80) with the
sleep midpoint used as a reference anchor for circadian time, early morning
light exposure was superior to late morning and to evening exposure.
Conclusion The antidepressant effect of light is potentiated by early-morning administration
in circadian time, optimally about 8.5 hours after melatonin onset or 2.5
hours after the sleep midpoint.
INTRODUCTION
THE FIRST controlled clinical trial of bright light treatment for seasonal
affective disorder (SAD)1 demonstrated a therapeutic
effect with daily exposures in the morning and evening. Since then there have
been numerous studies indicating an advantage of morning over evening light
exposure in cross-center pooling of data2 and
a Cochrane meta-analysis.3 Recently, 3 large
clinical trials have further established a benefit over nonphotic placebo
controls,4 the superiority of morning light
over evening light exposure,5 or both.6
The pathogenesis of SAD and mechanism of action of light remain uncertain
despite numerous investigations.7 A potential
role for abnormal circadian timing gained credence because the effects of
light (including phase shifting and melatonin suppression) had been well established
in both humans and animals. Lewy et al8, 9, 10
proposed that morning light would be effective because it provides corrective
phase advances of delayed circadian rhythms in patients with winter depression.
Although many studies have found that a shift to an earlier phase position
accompanies the antidepressant response to morning light5, 8, 10, 11, 12
or morning plus early evening light,13 a correlation
between the size of phase shifts and clinical improvement has not been demonstrated,14, 15, 16, 17, 18
which weakens the argument for a causal effect.
The present study, which used plasma melatonin onset as the circadian
phase marker, was designed with 3 questions in mind: (1) Do patients with
winter depression show contrasting phase shifts under morning and evening
light therapy? (2) Do those who are phase-typed as relatively delayed respond
preferentially to morning light? (3) Is treatment efficacy correlated with
the direction and magnitude of phase shifts?
SUBJECTS AND METHODS
SUBJECTS
Participants included 42 research volunteers aged 21 to 56 years (mean
± SD, 39.2 ± 9.3 years), with 29 women (69%) and 13 men (31%).
Intake evaluations were based on the Structured Clinical Interview for DSM-III-R,19 administered
by trained research staff. Diagnoses20—all
with seasonal pattern, winter type—were major depressive disorder, recurrent
(code 296.3) in 29 subjects (69%), and bipolar disorder not otherwise specified
(code 296.7) in 13 (31%). Candidates with comorbid Axis I disorders or recent
history of a suicide attempt were excluded. Subjects were part of a larger
group that underwent clinical trials of light therapy6
but were also available for evening or overnight laboratory sessions during
which blood was sampled for melatonin concentration. An expanded analysis
(N = 80) included 38 additional subjects from the complete group6
who provided sleep logs but not melatonin data.
PROCEDURE
Details of treatment have been previously described.6
Within a crossover design, 21 subjects first received morning light and then
evening light (M1E2), and 21 received treatment in the opposite order (E1M2).
Transitions were immediate, without withdrawals. After a minimum 2-week baseline
interval that verified a current depressive episode, subjects received 10
to 14 days of treatment in both periods, 30 minutes per day. Subjects were
instructed to maintain consistent bedtimes and wake-up times throughout the
study, according to their habitual schedule. They used the lights at home
either soon after awakening (6:32 AM ± 56 minutes) or approximately
2 hours before bedtime (9:30 PM ± 64 minutes). The lighting device
provided 10 000 lux, 2700°K fluorescent illumination through a 28
x 61-cm diffusing screen. Raters who were blinded to the treatment administered
the 29-item Structured Interview Guide for the Hamilton
Depression Rating Scale–Seasonal Affective Disorder Version (SIGH-SAD)21 at baseline and after both treatment
periods, on the same days melatonin was sampled.
Melatonin was sampled at 30-minute intervals in 2 protocols. Nine subjects
underwent 15-hour overnight sessions beginning approximately 4 hours before
their habitual sleep onset. Eight of these subjects completed 3 assessments,
at baseline and after both treatment periods, while the ninth declined reassessment
after baseline. Thirty-three subjects underwent 5-hour evening sessions after
which they returned home. Nineteen of these subjects completed all 3 assessments;
2 subjects whose baseline sessions were aborted for technical reasons completed
only posttreatment assessments; and 12 subjects were scheduled for and completed
only baseline and first-period assessments. Given these variations, we used
the maximum available sample size for each analysis.
Blood samples (4 mL) were obtained while subjects were seated or resting
in bed, using an indwelling venous catheter in the forearm. Ambient illumination
was 1 to 5 lux provided by a 15-watt shaded incandescent reading lamp. Subjects
commenced dim light exposure at least 1 hour before the first sample was collected.
Illumination remained constant across the sampling sessions except during
sleep when the light was extinguished.
Blood was centrifuged and plasma was separated and frozen for further
analysis. The plasma was subjected to a direct radioimmunoassay based on an
antiserum obtained from the University of Surrey, Guildford, England. The
assay was cross-validated against gas chromatography/mass spectrometry in
collaboration with A. J. Lewy, MD, PhD (Oregon Health Sciences University,
Portland). The comparison yielded a high correlation (r = 0.95; slope, 1.02; intercept, 5.7 pg/mL), and we achieved a lower
detectable limit of 2.5 pg/mL. In 8 consecutive analytical runs with 3 quality
control levels (22, 33, and 93 pg/mL), the within- and between-run relative
SD percentages were 10.4 and 14.6, 12.9 and 11.8, and 3.9 and 4.5, respectively.
STATISTICAL ANALYSIS
Rating scale scores were analyzed as raw data and in terms of the percentage
change from baseline. Univariate and multivariate analyses of variance and
covariance were used to detect group and group x period interactions
and the influence of baseline regressors. Linear regression, including forward
stepwise multiple regression (F to enter, 4.0; to remove, 3.996) and the correlation
coefficient, r, were used to measure the relationship
between continuous variables. Group means were compared by t tests and categorical differences by the  2 test.
For all statistical tests, an  level of .05 (2-tailed) served as the
criterion for significant differences.
To test a set of correlations between melatonin phase anchor points
across baseline, morning light, and evening light samples in overnight sessions,
the significance of the observed value was determined by reference to a random
probability distribution of correlations for all 8 permutations of subject
pairing, keeping conditions matched.
RESULTS
TIMING OF MELATONIN SECRETION AND SLEEP
Total melatonin production in overnight sessions did not differ under
baseline, morning light, and evening light conditions (grand mean ±
SD, 855 ± 588 pg.30min/mL; F2,14 = 1.92, P = .18), though there were significant interindividual differences
(F7,14 = 54.22, P = .001). The secretion
patterns were similar in shape (Figure 1).
Melatonin levels began to rise between 8 PM and 10 PM, reaching maximum concentration
between 1 AM and 4 AM, and returning to daytime levels between 8:30 AM and
10 AM. However, the curves were displaced from each other such that morning
light phase advanced the cycle and evening phase delayed it relative to baseline
(condition x time: F44,308 = 4.45, P<.001).
Phase determinations were based on 2 discrete markers: (1) the dim light melatonin
onset (DLMO) at a 10 pg/mL threshold, and (2) the time of melatonin synthesis
offset (SynOff) estimated by the last high-amplitude data point preceding
the steep early morning decline.22 The correlation
between DLMO and SynOff was high (r = 0.64, n = 23, P = .02 by randomization test; data were excluded in 1
case with an atypical secretion pattern). The 2 measures indicated similar
bidirectional phase shifts (DLMO vs SynOff for morning light, 1.51 ±
0.87 hours vs 1.25 ± 2.27 hours; for evening light, -1.34 ±
0.65 hours vs -1.29 ± 1.15 hours). We attribute the greater variability
of the SynOff shifts to determinations based on visual inspection.22 Because most subjects in the study underwent only
5-hour sampling in the evening, the DLMO was used as the phase marker in further
analyses.
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Figure 1. Mean plasma melatonin concentration
measured under dim light conditions (1-5 lux, with darkness during sleep)
at 30-minute intervals in overnight sessions at baseline and after 10 to 14
days of treatment with morning or evening light, presented in crossovers.
The 3 underlying curves for each of 8 subjects were normalized to compensate
for varying amplitude by weighting each data point by the grand mean area
under the curve.
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Figure 2 shows correlations,
all significant, between the baseline DLMO and sleep onset, offset, and derived
midpoints. The sleep midpoint, which shows the highest correlation (r = 0.66, n = 41, P<.001) and
slope of unity, can be used to predict an individual's DLMO with an SE of
±0.79 hours and maximum error across all data points of ±1.57
hours. Thus, with blood drawn at 30-minute intervals to determine the onset
of melatonin secretion, a sampling interval of 4.5 hours centered 6 hours
before the sleep midpoint would be expected to capture the DLMO with at least
1 adjacent subthreshold (<10 pg/mL) and suprathreshold (>10 pg/mL) value.
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Figure 2. Scatterplots (n = 41) of baseline
dim light melatonin onset (DLMO) vs 1-week averages of sleep onset and offset
(from subjects' daily sleep log records) and the derived sleep midpoint. The
highest correlation is between the DLMO and sleep midpoint, with the linear
regression equation y = 1.01x - 5.93, where y is the DLMO in decimal hours, x is the sleep midpoint,
and the intercept indexes the time delay between them.
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PHASE SHIFTS TO MORNING AND EVENING LIGHT
Twenty-seven subjects provided DLMO estimates at baseline and in both
legs of the morning-evening crossover. Baseline DLMOs were nearly identical
across groups (M1E2, 21:36 ± 1:12 hours; E1M2, 21:30 ± 1:06
hours). The magnitude of phase shift in either direction depended on the treatment
sequence (Figure 3). Phase advances
were larger when morning treatment followed evening treatment than following
baseline (1.31 ± 0.84 hours vs 0.74 ± 0.77 hours), while phase
delays were larger when evening treatment followed morning treatment than
following baseline (-1.25 ± 0.78 hours vs -0.71 ±
0.59 hours; group x period, F2,50 = 39.29, P<.001). The interaction was symmetrical, and posttreatment DLMOs
were indistinguishable regardless of the treatment sequence. Thus, further
analyses collapsed DLMO data within morning and evening treatment periods.
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Figure 3. Dim light melatonin onset (mean
± SD) at baseline and after 10 to 14 days of morning (M) and evening
(E) light treatment for subjects who completed a treatment crossover (M1E2,
n = 17; E1M2, n = 10).
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Both the direction and magnitude of phase shifts depended on the interval
between the baseline DLMO (or first-period DLMO preceding crossover) and the
time of light administration. Unlike the clock time of light exposure, the
DLMO-to-light interval provides a unifying metric for circadian time (CT).
In 59 (86.7%) of 68 cases, light exposure fell into clustered CT ranges (morning,
7.5 to 11 hours, 23 of 28 subjects; evening, -1.5 to 3 hours, 36 of
40 subjects) beyond which there was unsystematic scatter. In general, phase
delays increased the later the evening CT (r = -0.40,
n = 36, P = .01) while phase advances decreased the
later the morning CT (r = -0.50, n = 23, P = .008) with greatest advances occurring approximately
8-hours post-DLMO (Figure 4). There
was no significant effect when the same data were plotted against the clock
time of light exposure rather than CT (evening, r
= -0.17; morning, r = -0.19).
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Figure 4. Scatterplots of phase shifts as
a function of the circadian time (CT) of morning (n = 23) or evening (n =
36) light exposure, with linear regressions. The CT was specified as the interval
between melatonin onset preceding treatment and the midpoint of 30-minute
light exposures taken daily for 10 to 14 days.
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RELATION BETWEEN CIRCADIAN PHASE AND TREATMENT RESPONSE TO LIGHT
The study included 3 classes of dependent variables that might be interrelated:
melatonin phase shifts and changes in the timing of sleep (onset, midpoint,
offset, and duration) and in depression ratings. When morning and evening
light treatment were compared in a multivariate analysis of variance, there
was a significant overall effect (Wilks  = 0.33, F5,51
= 21.12, P<.001). Posttreatment DLMOs showed a
large, significant morning-evening contrast (Table 1). Although sleep onset showed no significant change, wake-up
was approximately 30 minutes earlier with a commensurate advance in the midpoint
and reduction in duration. By contrast, the percentage change in depression
ratings did not differ (morning, 58.8% ± 29.2%; evening, 57.9% ±
28.8%). Although remission rate (SIGH-SAD score of
8 or lower6) was higher for morning light than
evening light (14 [50.0%] of 28 vs 16 [40.0%] of 40), the difference fell
short of significance.
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Melatonin Onset and Sleep Parameters*
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There was a wide range of response (SIGH-SAD
change of -13% to 100%) obtained across phase shifts of -2.80
to 2.65 hours (Figure 5). Of subjects
who received morning light, 25 (89.3%) of 28 showed phase advances of the
DLMO, while 37 (92.5%) of 40 who received evening light showed phase delays
(21 = 45.49, P<.001).
In an analysis of variance of SIGH-SAD percentage
change with the DLMO phase shift as a covariate, there was no morning-evening
group effect (F1,64 = 0.34, P = .56) but
rather a significant interaction with the phase shift (F1,64 =
6.15, P = .02). Figure 5 locates this interaction to the morning light condition,
under which there was a positive correlation between improvement and the size
of phase advance (r = 0.44, n = 28, P = .02), while there was no significant correlation for evening light
(r = -0.17, n = 40, P
= .29). Although the morning light effect accounts for only 19.4% of the variance,
the regression line indicates a 2-fold change in response, from approximately
40% to 80% between the smallest and largest phase shifts.
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Figure 5. Scatterplots of baseline-to-posttreatment
percentage change in depression rating scale scores (Structured Interview
for the Hamilton Depression Rating Scale–Seasonal Affective Disorder
Version [SIGH-SAD]21) vs the phase shift
of melatonin onset (negative values, delays; positive values, advances) obtained
after morning (n = 28) or evening (n = 40) light exposure. Linear regressions
for the 2 treatment times disregard the direction of obtained phase shifts.
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There was no significant correlation between (1) baseline DLMO and severity
of depression (SIGH-SAD score); (2) baseline DLMO
and percentage change in SIGH-SAD score after first-period
treatment with morning or evening light; and (3) posttreatment DLMO and SIGH-SAD change. Thus, we were able to rule out circadian
phase position—in contrast with phase shifts—as a factor determining
treatment response.
We sought corroboration of the morning light phase shift effect in a
larger sample that received parallel group, first-period treatment in the
main clinical trial.6 Remission rate under
morning light (24 [58.5%] of 41) was nearly twice that under evening light
(12 [30.8%] of 39; 21 = 6.23, P = .02). Given the absence of melatonin data in roughly half of this
group, we derived the CT of light administration from the baseline sleep midpoint
(Figure 2). Under morning light
there was a significant correlation between CT and the percentage change in SIGH-SAD score (r = –0.38, P = .01) that was absent under evening light (r = –0.03). When the morning group was split according to the
median CT (earlier or later than 9.53 hours after the estimated DLMO), the
early CT group showed a large, significant advantage (SIGH-SAD percentage change, 75.6% ± 16.4% vs 52.5% ± 29.8%, P = .004; remission, 16 [80.0%] of 20 vs 8 [38.1%] of 21, 21 = 7.41, P = .007). When compared
with the response to evening light (percentage change, 54.1% ± 30.1%;
remission, 12 [30.1%] of 39), early-morning CT also showed distinct superiority
(percentage change, P = .002; remission, 21 = 12.85, P<.001), while late-morning
CT and evening light were not significantly different.
PHASE SHIFTS OF SLEEP-WAKE VS MELATONIN RHYTHMS
The antidepressant effect of morning light might be attributed to the
DLMO phase advance or accompanying sleep changes. We performed forward stepwise
multiple regressions for SIGH-SAD percentage change
separately for morning and evening light, which included all the sleep measures
and DLMO change. Under morning light the DLMO phase advance was the only measure
retained in the model (F1,26 = 6.09, P
= .02). Notably, wake-up time was excluded. Under evening light, none of the
variables was retained in the model. We conclude that sleep changes did not
affect clinical response.
An elaboration of the phase shift hypothesis attributes improvement
to changes in the phase angle difference (PAD) between sleep and other circadian
rhythms (eg, of melatonin), rather than to the circadian phase shift alone.9 In pretreatment to posttreatment comparisons, the
interval between melatonin and sleep onset increased by 0.90 ± 0.81
hours under morning light (P<.001), placing the
DLMO 2.45 ± 1.25 hours before sleep. By contrast, under evening light
the interval decreased by -0.90 ± 0.75 hours (P<.001), placing the DLMO 1.22 ± 1.21 hours before sleep.
The SIGH-SAD percentage change was significantly
correlated with the change in PAD ( PAD) under morning light (r = 0.42, n = 28, P = .03), which
mirrors the correlation with DLMO change alone (r
= 0.44, Figure 5). Under evening
light, improvement was not significantly correlated with the PAD (r = -0.20, n = 40, P = .22).
Furthermore, PADs computed against the sleep midpoint and wake-up time
showed no relationship with clinical improvement under either morning or evening
light.
COMMENT
This study demonstrates that morning and evening light exposure at 10 000
lux, 30 minutes per day produces phase shifts of the melatonin rhythm consistent
with human phase response curves (PRCs)23, 24
and other morning-evening comparisons.8, 25
Two laboratory PRC paradigms have presented light pulses across the circadian
cycle under free-running conditions (5000 lux, 3-hour exposure on a single
day or 3 consecutive days)24 or constant routines
(10 000 lux, 3 days).23 By contrast, we
generated discrete delay and advance portions of the PRC at the edges of the
subjective night, which represented the cumulative effect of 10 to 14 daily
30-minute light exposures in subjects who maintained habitual sleep-wake cycles
and entrainment in their normal living environment. Delays up to 2.80 hours
occurred after evening light exposure, and advances up to 2.65 hours occurred
after morning light exposure, depending on the CT of exposure relative to
the pretreatment DLMO. When PRCs are measured throughout the night—a
procedure incompatible with habitual sleep—there is a crossover between
delays and advances before the time subjects normally awaken, around the nocturnal
core body temperature minimum,23 which closely
matches the SynOff.26 In our situation we predict
that light presentation earlier than 7.5 hours post-DLMO would yield smaller
phase advances and lower antidepressant efficacy, with a crossover to phase
delays corresponding to the SynOff in our overnight samples, 7.17 ±
1.25 hours post-DLMO. Direct measurement of the crossover point would require
that subjects awaken at earlier CT than in this study, or possibly receive
illumination while asleep.27
Although it was initially hypothesized that patients with winter depression
would show delayed circadian rhythms relative to normal control subjects,
results have been equivocal, both positive5, 8, 10, 11, 12
and negative.14, 16, 18, 28, 29
Our study lacked a normal control comparison, yet we found that following
morning light, patients who were relatively phase delayed at baseline did
not show greater improvement in depression scores. Three other studies14, 15, 30 also found no relationship
between baseline circadian phase and clinical improvement. Rather, we have
shown the size of phase advance relative to baseline (or advance relative
to sleep onset) to be key.
Our protocol did not impose a standard clock time for sleep (or for
light exposure) as in earlier studies,8 but
rather allowed individual subjects to follow their habitual sleep schedule.
A corollary of the phase shift hypothesis is that the crucial determinant
of antidepressant efficacy is the PAD between sleep and other circadian
rhythms (eg, melatonin).9 Indeed, the key may
lie in the phase relation between sleep and the circadian rhythm of mood,
which recently has been demonstrated in patients31
and healthy subjects32 using rating scales.
Since sleep onset did not change after light treatment in our study, the PAD
resulted simply from the DLMO phase shift. A related study found that morning
light produced a smaller phase advance of sleep than of the melatonin rhythm,
but overall the PAD was minimal despite a therapeutic response.33 While the PAD in our study was significantly
correlated with the therapeutic response under morning light, response did
not vary with the PAD itself (2.45 ± 1.26 hours; range, -0.35
to 4.25 hours). Thus, although treatment succeeded in expanding the PAD, we
cannot identify an optimum posttreatment interval associated with euthymia.
Based on the present melatonin data, one would conclude that a phase
advance is neither necessary nor sufficient for the therapeutic effect because
the remission rates for morning light and evening light were not significantly
different. Other studies have also sought a correspondence between phase shifts
and clinical response and were unable to distinguish responders from nonresponders
on this basis.14, 15, 18, 34
However, all of these studies have been limited by the sample size used to
assess the antidepressant effect, which has inherently high variance. Notably,
3 larger studies,4, 5, 6
one including the present subjects,6 have demonstrated
morning light superiority.
The increased power of larger samples seems necessary to overshadow
the nonspecific benefits of evening light exposure.4, 6
When we expanded the parallel groups' sample in the present study, for example,
morning light superiority was clearly located to an early CT exposure interval
that would serve to magnify phase advances. In the present crossover groups
(M1E2 and E1M2), we expected to find greater antidepressant response in M2
than M1, since M2 phase shifts were larger. However, although the remission
rate was twice as high in M2 (6 [60%] of 10 vs 5 [29.4%] of 17), the small
sample size prevented detection of a significant difference (21 = 2.44, P = .12). Rather than recommending
that patients initially be given a phase delay by evening light to magnify
the phase advance to morning light, an implication of the parallel group analysis
is that the antidepressant effect of M1 can be directly enhanced by light
exposure at earlier CT. For long sleepers this would require waking up for
light therapy before habitual rise time.35
A novel finding of our study is the correlation between the magnitude
of phase advances to morning light and improvement in depression ratings.
Such results confirm the hypothesis of Lewy and Sack and colleagues,8, 10 who also showed that improvement under
morning light is coincident with a group mean phase advance of the DLMO, although
they did not find a correlation between size of the advance and antidepressant
response across individuals. The results do not confirm our earlier hypothesis36 that light would be efficacious unless it induces
a phase delay. Patients with large phase delays to evening light were no more
depressed than those with smaller delays or those with small advances to morning
light.
A signal detection analysis of morning vs evening light response6 showed maximum group contrasts at criteria of 70%
to 100% improvement in SIGH-SAD score, or a final
score between 0 and 8. In the present study, such strong response is associated
with phase advances to morning light of approximately 1.5 to 2.5 hours, obtained
at DLMO-to-light intervals of 7.5 to 9.0 hours. If the response to evening
light were no more than a placebo effect, as has been proposed,5
the specific efficacy of morning light could be attributed to phase advances
of at least 1.5 hours.
The early-CT advantage of morning light exposure seems to be key to
the specific efficacy of this treatment modality. This interpretation is strengthened
by the fact that subjects had no knowledge of their DLMOs or the CT of light
exposure, yet responded in a phase-shift dependent manner. Further research
is needed to determine whether evening light (or morning light at late CT)
exerts an antidepressant effect beyond that of placebo. The most convincing
analysis4 used an inert nonphotic control (a
dummy negative ionizer) with response rates and expectation ratings no different
from those under evening light. In a related trial,6
response rate was higher for evening light than for low-density ionization,
but expectations also were higher. Other studies supporting evening light
efficacy have lacked adequate placebo controls, with conclusions mainly based
on nonsignificant differences from morning or midday light treatment.
In conclusion, we recommend that for maximum advantage, light therapy
of 10 000 lux for 30 minutes should be scheduled in circadian rather
than clock time, about 8.5 hours after the baseline DLMO. A DLMO phase diagnostic
is not yet readily available in clinical practice. However, the DLMO can be
inferred within an acceptable margin of error from the self-reported sleep
midpoint (Figure 2). This algorithm
does not apply to people who sleep "out of phase" with their circadian clock,
such as shift workers, but is confined to stable sleepers with 6 to 9 hours
duration, onset between 10:00 PM and 1:00 AM, and waking between 5:30 AM and
9:00 AM. By consulting a derived table,35 the
clinician can select an appropriate treatment time which then can be adjusted
depending on the patient's initial response.
AUTHOR INFORMATION
Accepted for publication May 15, 2000.
This research was supported by grant 5 RO1 MH42931 from the National
Institute of Mental Health, Bethesda, Md.
Preliminary data were discussed by Dr M. Terman at the Banbury Center
Conference on Melatonin: Mechanisms and Action, Cold Spring Harbor Laboratory,
Cold Spring Harbor, NY, April 10-13, 1994. In addition, data were summarized
in his chapter "On the Specific Action and Clinical Domain of Light Therapy"
in Seasonal Affective Disorder and Beyond: Light Treatment of SAD and Non-SAD
Conditions (Lam RW, ed. Washington, DC: American Psychiatric
Press; 1998:91-115).
We wish to thank Donald C. Ross, PhD, for statistical guidance.
From the Clinical Chronobiology Program (Drs J. Terman and M. Terman),
and the Department of Analytical Psychopharmacology (Dr Lo and Mr Cooper),
New York State Psychiatric Institute, New York, and the Department of Psychiatry
(Dr M. Terman), Columbia University, New York.
Corresponding author and reprints: Michael Terman, PhD, New York
State Psychiatric Institute, 1051 Riverside Dr, Unit 50, New York, NY 10032
(e-mail: mt12{at}columbia.edu).
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