Morning vs evening light treatment of patients with winter depression.

Abstract

According to the phase-shift hypothesis for winter depression, morning light (which causes a circadian phase advance) should be more antidepressant than evening light (which causes a delay). Although no studies have shown evening light to be more antidepressant than morning light, investigations have shown either no difference or morning light to be superior. The present study assesses these light-exposure schedules in both crossover and parallel-group comparisons.
Fifty-one patients and 49 matched controls were studied for 6 weeks. After a prebaseline assessment and a light/dark and sleep/wake adaptation baseline week, subjects were exposed to bright light at either 6 to 8 AM or 7 to 9 PM for 2 weeks. After a week of withdrawal from light treatment, they were crossed over to the other light schedule. Dim-light melatonin onsets were obtained 7 times during the study to assess circadian phase position.
Morning light phase-advanced the dim-light melatonin onset and was more antidepressant than evening light, which phase-delayed it. These findings were statistically significant for both crossover and parallel-group comparisons. Dim-light melatonin onsets were generally delayed in the patients compared with the controls.
These results should help establish the importance of circadian (morning or evening) time of light exposure in the treatment of winter depression. We recommend that bright-light exposure be scheduled immediately on awakening in the treatment of most patients with seasonal affective disorder.

Full text

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Morning vs Evening Light Treatment of Patients
With Winter Depression
Alfred J. Lewy, MD, PhD; Vance K. Bauer, MA; Neil L. Cutler, BA; Robert L. Sack, MD;
Saeeduddin Ahmed, MD; Katherine H. Thomas, MD; Mary L. Blood, MS; Jeanne M. Latham Jackson, MD
Background: According to the phase-shift hypoth-
esis for winter depression, morning light (which
causes a circadian phase advance) should be more
antidepressant than evening light (which causes a
delay). Although no studies have shown evening light
to be more antidepressant than morning light, investi-
gations have shown either no difference or morning
light to be superior. The present study assesses these
light-exposure schedules in both crossover and
parallel-group comparisons.
Methods: Fifty-one patients and 49 matched controls
were studied for 6 weeks. After a prebaseline assess-
ment and a light/dark and sleep/wake adaptation base-
line week, subjects were exposed to bright light at ei-
ther 6 to 8 AM or 7 to 9 PM for 2 weeks. After a week of
withdrawalfromlighttreatment,theywerecrossedover
to the other light schedule. Dim-light melatonin onsets
were obtained 7 times during the study to assess circa-
dian phase position.
Results:Morninglightphase-advancedthedim-lightmela-
toninonsetandwasmoreantidepressantthaneveninglight,
which phase-delayed it. These findings were statistically
significantforbothcrossoverandparallel-groupcompari-
sons. Dim-light melatonin onsets were generally delayed
in the patients compared with the controls.
Conclusions:Theseresultsshouldhelpestablishtheim-
portanceofcircadian(morningorevening)timeoflight
exposure in the treatment of winter depression. We rec-
ommendthatbright-lightexposurebescheduledimme-
diately on awakening in the treatment of most patients
with seasonal affective disorder.
Arch Gen Psychiatry. 1998;55:890-896
T
thal and coworkers4coined the term sea-
sonal affective disorder (SAD) for this dis-
order, described its clinical features, and
conducted the first controlled investiga-
tioninwhichcomparativelydimlightwas
used as a placebo control. A form of re-
current depression marked by an annual
onset from midautumn to early winter,
SAD may affect more than 10 million
Americans.5Itsprevalenceisgreatestinfe-
males, and it is often accompanied by
atypical symptoms of fatigue, hypersom-
nia,carbohydratecraving,andweightgain.
AmongthefirsthypothesesforSAD6,7
is the phase-shift hypothesis (PSH),8-10
which postulates that bright light is anti-
depressant in patients with SAD at least
in part by causing a circadian phase ad-
vance. It is well established that bright-
light exposure in the morning causes a
HE DISCOVERY that human
melatonin production can
be suppressed by bright
light1led to the initial test
of bright light in treating
winterdepression.2,3Subsequently,Rosen-
phase advance and in the evening causes
a phase delay.8,9,11-18Critical to the PSH is
thatbright-lightexposureshouldbemore
antidepressantwhenitisscheduledinthe
morning than when it is scheduled in the
evening, because most patients with SAD
areexpectedtohavephase-delayedcirca-
dian rhythms when depressed in the
winter. However, some clinicians recom-
mend exposure at other times of the day,
particularly if morning is not conve-
nient.19Therefore, for both practical and
theoreticalreasons,itisimportanttoknow
ifcircadiantimeofexposureaffectslight’s
antidepressant efficacy.
Therearenoinvestigationsthatdem-
onstrateeveninglight(EL)tobemorean-
tidepressant than morning light (ML).
Studies are divided between those that
show ML to be superior and those that
show no difference (see the “Comment”
See also pages 861,
863, 875, and 883
ORIGINAL ARTICLE
From the Sleep and Mood
Disorders Laboratory,
Department of Psychiatry,
Oregon Health Sciences
University, Portland. Dr Ahmed
is now with the Palo Alto
Health Care System, Palo Alto,
Calif.
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section). This may be similar to the pharmacological lit-
erature,inwhichantidepressantmedicationhasbeenshown
to be superior or equal, but rarely inferior, to placebo.
Morning light has been found to be more antide-
pressant primarily in crossover studies, whereas most
parallel-group studies have failed to demonstrate a sta-
tistically significant benefit of ML. The following inves-
tigationstudiedalargenumberofpatients,soastohave
sufficientpowertoassessMLvsELinbothparallel(first
treatment period) and crossover comparisons. We hy-
pothesized that ML would be more antidepressant
than EL.
RESULTS
Fifty-one patients with SAD (45 women) and 49 con-
trols (40 women) completed the study. There was mini-
malminorityrepresentation.CompleteDLMOsetswere
SUBJECTS AND METHODS
SUBJECTS
After approval by the institutional review board at Oregon
Health Sciences University, Portland, the study was
conducted each January and February during 4 winters
(1989-1992) in Portland, (45°N latitude). Subjects were
recruitedthroughadvertisementsinareanewspapers,tele-
vision interviews, and referrals from health professionals.
About 1900 patients were sent a Seasonal Pattern Assess-
ment Questionnaire,20a 21-item Beck Depression Inven-
tory,21and a health and sleep screening questionnaire that
inquiredaboutmedicalandpsychiatrichistory.Morethan
80 potential subjects were interviewed.
To be admitted into the study, all patients had to (1)
meet DSM-III-R criteria22for moderate to severe major de-
pressive disorder (without psychotic episodes) or bipolar
disorder (depressed or not otherwise specified) with a
winter-typeseasonalpattern;(2)score20orhigheronthe
Structured Interview Guide for the Hamilton Depression
Rating Scale–Seasonal Affective Disorder Version (SIGH-
SAD)23with a Hamilton Depression scale24score of 10 or
more and an atypical score of 5 or more25; (3) report that a
depression developed during the fall or winter and remit-
ted the following spring for at least the 2 preceding years;
(4) be in good physical health; (5) not be suicidal; (6) not
haveusedpsychotropicmedicationsfortheprevious4weeks
orothermedicationsthatinterferewithendogenousmela-
tonin production; and (7) not have other psychiatric or
medical illnesses. Control subjects did not have notable
medical or psychiatric problems (including seasonal fluc-
tuations in mood, sleep, appetite, and energy) and were
taking no medications that could interfere with mood or
endogenous melatonin production.
A total of 56 patients and 52 controls participated.
Two patients did not complete the study, 3 were found to
have other psychiatric problems after beginning the study,
and 2 had immeasurable melatonin levels (which are
excluded from any dim-light melatonin onset [DLMO]
analyses). Three controls did not complete the study.
Controls and patients were matched by age and sex as
closely as possible. Informed consent was obtained from
all participants.
LIGHT TREATMENT
The light fixtures contained two 40-W cool-white fluores-
cent tubes (Hughes Lighting Technologies, Lake Hopat-
cong, NJ). To determine the distance to obtain 2500
lux, intensities were measured for each light fixture using
a light meter with a photometric sensor. Subjects were
instructed to sit 45° to the light with their eyes at midfix-
turelevelandtogazeacrossitonceortwiceaminute,rather
than stare directly at it.
A prebaseline assessment was followed by a baseline
week,2weeksofafirstin-homelighttreatmentperiod(I-1
andI-2),awithdrawalweek,and2weeksofasecondlight
treatment period (II-1 and II-2). Subjects were assigned to
receive either ML first (6 to 8 AM; MLF group) or EL first
(7 to 9 PM; ELF group), balanced for age, sex, and pre-
baseline SIGH-SAD rating. Before the study, subjects were
asked whether they thought ML or EL would be more an-
tidepressant, equally antidepressant, or make no differ-
ence;theycouldalsoanswer“don’tknow.”Duringthestudy,
subjects were asked to avoid unscheduled bright-light ex-
posure(suchasinthesupermarket)from6 PMto8 AMand
nottotraveloutsidethetimezone.Subjectswerealsoasked
to maintain a 10 PM to 6 AM sleep schedule and to com-
plete a written daily sleep and mood diary. For most sub-
jects, sleep diary data were also obtained for 2 weeks be-
fore entry into the study. Morning wake-up times were
verifiedeachdaybyhavingsubjectscallthelaboratoryand
leave a voice-mail message.
MELATONIN
Subjects were admitted to the Clinical Research Center at
Oregon Health Sciences University for a prebaseline visit
followedby6weeklyvisitsforassessmentoftheDLMO(a
very reliable marker of circadian phase position26) and be-
havioral(29-itemSIGH-SAD)ratingsby2independentblind
raters (including, at times, N.L.C., M.L.B., and J.M.L.J.).
SubjectsalsocompletedaBeckDepressionInventoryeach
week.Underdimlight(?50lux),bloodsamples(3-5mL)
were drawn every 30 minutes from 6 to 11 PM (sometimes
later). (Dim light is necessary in sighted people to avoid
theacutesuppressanteffectoflightonmelatonin1;wecur-
rently recommend light intensities of ?30 lux for the
DLMO.)Sampleswereimmediatelycentrifuged,andplasma
was separated and frozen for later analysis. Melatonin was
assayed by means of a modification of the highly sensitive
and specific gas chromatographic–negative chemical ion-
ization mass spectrometric method.27The DLMO was de-
fined as the first interpolated point above 10 pg/mL that
continued to rise.
STATISTICS
For continuous data, repeated-measures analyses of vari-
ance (ANOVAs) were performed, followed by group or
paired t tests, where appropriate. For categorical data, ?2
and Fisher exact tests were used. Unless otherwise stated,
results described as statistically significant refer to P?.05
on a 2-tailed test.
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Page 3

obtainedforallofthecontrolsand49ofthepatients.The
mean±SDageofthepatientswas40.2±8.9years(range,
25-61 years), while that of the controls was 38.3±11.1
years(range,22-68years).Twenty-sevenpatientsand24
controls received MLF, and 24 patients and 25 controls
received ELF.
SIGH-SAD RATINGS
The SIGH-SAD scores throughout the study by treat-
ment group are shown in Figure 1. A repeated-
measures ANOVA was performed on the patient 29-
itemSIGH-SADscores,withorderoftreatment(MLFor
ELF) as the grouping variable and treatment as the re-
peatedmeasure(baseline,withdrawal,ML,andEL).The
firstweekoflighttreatmentwasnotincludedinanyanaly-
ses. A main effect was found for treatment (F3=23.14,
P?.001) and for order of treatment (F1=4.53, P=.04).
The interaction was not significant.
Previous crossover studies have reported an order
effect, in which EL is more effective when administered
asanoveltreatmentthanwhenitfollowstreatmentwith
ML.25In our data, there is the suggestion of such an ef-
fect,inthatMLratingswerenotsignificantlylowerthan
EL ratings in the first treatment period but were so in
the second treatment period (t49=3.44, P=.001). How-
ever,posttreatmentratingsdidnotsignificantlydifferbe-
tween the 2 treatment periods. Furthermore, with-
drawalweekratingswerenotdifferentfrombaselineweek
ratings, which indicates that no carryover resulted from
light treatment. Change scores were calculated by sub-
tracting posttreatment ratings from those of the appro-
priatebaselineorwithdrawalweek.Whenchangescores
were combined for the first and second treatment peri-
ods(Table 1),thedecreaseinratingsafterMLwastwice
that of EL.
CombiningSIGH-SADscoresofbothMLFandELF
groups, ML ratings (17.45 ± 12.2) were 37% lower
(t50=7.38,P?.001)thantheappropriatepretreatmentrat-
ings (27.68±9.17), and EL ratings (23.95±10.39) were
17%lower(t50=3.58,P?.001)thantheappropriatepre-
treatmentratings(28.82±8.18).TheMLratingswere27%
lower than EL ratings (t50=3.26, P=.002).
Remission criteria (?50% decrease in 29-item
SIGH-SAD ratings to a posttreatment score of ?14, a
Hamilton Depression scale score of ?7 with an atypical
score of ?7, or a Hamilton Depression scale score ?2
with an atypical score ?10)25indicated that 19 (37%)
of the 51 patients responded after ML, while only 3
(6%) did after EL. Two of these patients also met crite-
ria after ML, leaving only 1 who responded exclusively
to EL. These findings were statistically significant
(?2=20.65, P?.001).
For the first treatment period (the parallel-group
comparison), change scores (Table 1) in the MLF group
were more than twice those of the ELF group
(10.35±10.71vs4.75±9.13;t49=1.99,P=.05);percent-
age change scores from baseline were 36% for ML com-
pared with 8% for EL (t49=2.09, P=.04). Of the 27 pa-
tients in the first treatment period, 8 (30%) responded
after ML, while only 1 did after EL (?2=6.88, P=.008).
IntheMLFgroup,withdrawalweekratingsweresignifi-
cantly (t26=5.40, P?.001) greater than ML ratings, in-
dicatingthatthesepatientsrelapsed,whereaspatientsin
the ELF group did not significantly worsen during the
withdrawalweek.BeckDepressionInventoryscoreswere
generally consistent with the above findings.
MELATONIN ANALYSIS
A repeated-measures ANOVA was performed on pa-
tients’andcontrols’DLMOswithtreatmentastherepeated
40
30
35
25
15
20
10
0
5
Prebaseline PrebaselineBaselineML1ML2
MLF Patients
WithdrawalEL1EL2
SIGH-SAD Score (Mean + SD)
Baseline EL1 EL2 WithdrawalML1ML2
AB
ELF Patients
Figure 1. Patient behavioral ratings on the Structured Interview Guide for the Hamilton Depression Rating Scale–Seasonal Affective Disorder Version (SIGH-SAD)
for patients who received morning light first (MLF) and evening light first (ELF). ML1 and ML2 indicate weeks 1 and 2, respectively, of morning light treatment;
EL1 and EL2, weeks 1 and 2, respectively, of evening light treatment.
Table 1. Decrease in SIGH-SAD Scores After EL and ML*
ML EL
MLF patients (n = 27) 10.35 ± 10.714.98 ± 10.42
t26= 1.68, P = .11
ELF patients (n = 24)10.08 ± 9.13 4.75 ± 9.13
t23= 1.90, P = .07
Total10.23 ± 9.90 4.87 ± 10.71
t50= 2.52, P = .02
*Data are presented as mean ± SD, compared with baseline or withdrawal
weeks. Abbreviations are explained in the legend to Figure 1.
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measure.Asmentionedabove,thefirstweekoftreatment
inbothtreatmentperiodswasexcludedinthestatisticalanaly-
ses.Maineffectswerefoundfortreatmentweek(F3=191.53,
P?.001)andforgroup(ie,patientsweredelayedcompared
withcontrols)(F1=5.04,P=.03).Theinteractionwasnot
significant.Next,arepeated-measuresANOVAwasperformed
withorderoftreatmentasthegroupingvariableandweek
oftreatmentastherepeatedmeasure.Forpatients,therewas
amaineffectfororderoftreatment(F1=9.09,P=.004)and
fortreatmentweek(F3=105.02,P?.001).Theinteraction
wasalsosignificant(F3=3.93,P=.009).Forcontrols,amain
effect was not found for order of treatment but was found
fortreatmentweek(F3=96.34,P?.001).Theinteractionwas
not significant.
Patientsweredelayedcomparedwithcontrolsatall
weeks of the study (F1=4.59, P=.03) (Figure 2). This
was mainly because of the MLF patient group. Table 2
shows the mean DLMO times at prebaseline, as well as
for the baseline and withdrawal weeks.
Both patients (t48=6.41, P?.001) and controls
(t48=6.98,P?.001)advancedafterthebaselineweek(Fig-
ure 2), probably because of natural light exposure earlier
inthemorning.Relativetobaselineandwithdrawalweeks,
theadvanceresponsetoMLandthedelayresponsetoEL,
respectively,werestatisticallysignificantforbothpatients
(t48=9.23, P?.001 and t48=6.88, P?.001) and controls
(t48=9.53,P?.001andt48=5.99,P?.001).Withdrawalweek
DLMOscamebacktotheirbaselinetimesforbothpatients
and controls.
SLEEP MEASURES
These will be reported on more extensively in another
publication, as well as analyses of more esoteric vari-
ables (eg, phase-angle differences). In the patients, EL
sleeponsetwas31minuteslaterthanwithML(t44=6.51,
P?.001),andMLsleepoffsetwas19minutesearlierthan
withEL(t44=4.23,P?.001).TotalsleeptimeafterELwas
not different from that after ML.
PATIENT EXPECTATIONS
Atthebeginningofthestudy,wewereabletoobtainex-
pectation ratings in 44 of the patients. Most patients (26
[59%]) thought that ML would be more antidepressant
than EL (Figure 3). However, there was no relation-
ship between this expectation and actual response
(?2=2.32, Fisher exact P=.22); while 16 of 26 patients
who expected ML to be more antidepressant did better
withML,only1of9patientswhothoughtthatELwould
be more antidepressant did better with EL.
24
22
23
21
19
20
18
MLF Patients
DLMO, h
AB
ELF Patients
24
22
23
21
19
20
18
Prebaseline PrebaselineBaselineML1 ML2
MLF Controls
WithdrawalEL1EL2
DLMO, h
Baseline EL1EL2 WithdrawalML1ML2
CD
ELF Controls
Figure 2. Dim-light melatonin onset (DLMO) times (and SDs) for patients and controls who received morning light first (MLF) and evening light first (ELF). Other
abbreviations are explained in the legend to Figure 1.
Table 2. Pretreatment DLMO Times
for Patients and Controls*
ControlsPatients
Prebaseline21:05 ± 0:5921:37 ± 1:33
t96= 2.08, P = .04
Baseline20:35 ± 0:5420:57 ± 1:16
t96= 1.60, P = .11
Withdrawal 20:24 ± 0:5120:50 ± 1:05
t96= 2.16, P = .03
*DLMO indicates dim-light melatonin onset, in clock time
(hours:minutes).
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Page 5

COMMENT
This study clearly shows that ML is at least twice as an-
tidepressant as EL in the treatment of SAD. An order or
carryover effect has been raised25,28-31as a potential con-
founder in crossover studies, but it does not appear to
be a problem in the present study.
Most,9,32,33but not all,34investigations that demon-
strated ML superiority were crossover studies, whereas
mostpreviousinvestigationsthatfoundnodifferencebe-
tween ML and EL were of the parallel-group type.31,35-37
Whenpresent,theordereffectwasthefollowing:thean-
tidepressantsuperiorityofMLoverELwasgreaterinthe
second treatment period than in the first treatment pe-
riod. In the present study, we found only a slight order
effect,whichwasnotthesameasreportedbyothers,and
there was no evidence of a carryover effect. Perhaps this
was because of the withdrawal week between treatment
periods. It should also be mentioned that there was no
significant interaction between treatment and order of
treatment on the ANOVA.
In any event, ML was more antidepressant than EL
wheneachtreatmentperiodwasanalyzedseparately,in-
cluding the first treatment (parallel-group) compari-
son.Furthermore,MLwasmoreantidepressantthanEL
in the entire (crossover) data set. Together with 2 other
recent,large-sample,parallel-groupinvestigations,37,38the
present study will, we hope, help end whatever doubts
remain about ML’s antidepressant superiority.
Our expectation data are probably open to differ-
ent interpretations. Half of the patients expected ML to
be more efficacious than EL, whereas only 9 expected
EL to be more efficacious. On the other hand, these
expectations did not correctly predict the response to
light treatment. Only slightly more than half of the
patients who responded best to ML predicted this accu-
rately, and in the case of EL, the antidepressant
response actually went in the opposite direction from
that expected (Figure 3).
In this and in 1 of our previous studies,33EL rat-
ings were lower than those at baseline. Why does EL
not make patients more depressed than at baseline?
One explanation might be that EL’s placebo component
is greater than its depressant (phase-delay) component,
so that its net effect is somewhat efficacious. The same
placebo component is presumably present in ML, but in
this case the 2 effects are additive, perhaps limited by an
overall ceiling.
Indeed,lackofaplacebocontrolinthepresentstudy
calls into question our finding that EL ratings were sig-
nificantly lower than baseline ratings. To date, 1 study
has shown EL to be more effective than a credible pla-
cebo control38and 1 study has not.39If EL is eventually
shown to be an effective antidepressant compared with
a credible placebo control, then it would be reasonable
toconcludethatlighthasmorethan1mechanismofac-
tion for its antidepressant efficacy, such as an “energiz-
ingeffect.”40However,aslongasMLisshowntobemore
antidepressantthanEL,thePSHwillremainaviableex-
planation for 1 of light’s antidepressant effects.
Lack of a credible placebo control seriously con-
founds interpretation of studies that found no differ-
enceinantidepressantefficacybetweenMLandEL(these
studies are reviewed elsewhere31,40). For example, in a
large-sample investigation in which ML and EL were
found to be equally antidepressant when administered
in parallel to separate groups of patients,31raters were
presumablyblindonlyastotimeoflightexposure.Thus,
in this study raters could have enabled a bias that time
of light exposure is not important by rating all patients
as improved whenever they were exposed to light.
Ofsomeconcerninthepresentinvestigationisthat
the patients do not appear to be as phase-delayed as in
previous studies. Two of 3 assessments showed patients
to be phase-delayed compared with controls, whereas 1
would have barely achieved statistical significance on a
1-tailed test (Table 2). There were also small changes in
sleeptimes,whichcannotberuledoutasinfluencingde-
pression ratings in this study.
However, if ML were more antidepressant merely
becauseithelpedpatientsadaptbettertotheearliersleep
schedule, we should have found more of a benefit of ML
than EL in the first treatment period than in the second
treatment period (such was not the case). Similarly, pa-
tients should have worsened during their adaptation to
the earlier sleep schedule of the first baseline week, and
these ratings should have been higher than those of the
withdrawal week; on the contrary, ratings during the 3
nontreatment weeks were virtually identical. Further-
more,2otherrecentlarge-samplestudiesinwhichsleep
wasstabilizedaccordingtohabitualschedulesfoundML
to be superior to EL.38,39
A more detailed analysis of the rather complicated
interactions between the DLMO, sleep times, behav-
ioral ratings, and other variables will be the subject of
anotherreport.However,preliminaryanalysesdonotdis-
close anything that would change the major findings of
the present study.
Phasedelayshavebeenreportedinpatientswithwin-
ter depression compared with controls in some stud-
ies,9,33,41but not in others,42and no study has reported a
30
10
20
0
–20
–10
–30
MLEL EitherDid Not Know
Pretreatment Expectation
Treatment Response (EL2 – ML2)
Responded to EL
Responded to ML
Figure 3. Results of the expectation questionnaire. Patients were asked,
“Which would you think would be more effective in the treatment of winter
depression, light early in the day or late in the day, or that it would make no
difference (if you absolutely have no idea and cannot give a best guess,
check ‘don’t know’)?” ML indicates morning light, and EL, evening light.
Treatment response was determined by the score on the Structured
Interview Guide for the Hamilton Depression Rating Scale–Seasonal Affective
Disorder Version23after the second week of ML (ML2) subtracted from that
after the second week of EL (EL2).
ARCH GEN PSYCHIATRY/VOL 55, OCT 1998
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©1998 American Medical Association. All rights reserved.