Michael Terman, PhD; Jiuan Su Terman, PhD; Donald C. Ross, PhD
Background: Artificial bright light presents a promising nonpharmacological
treatment for seasonal affective disorder. Past studies, however, have lacked
adequate placebo controls or sufficient power to detect group differences.
The importance of time of day of treatment—specifically, morning light
superiority—has remained controversial.
Methods: This study used a morning × evening light crossover design
balanced by parallel-group controls, in addition to a nonphotic control, negative
air ionization. Subjects with seasonal affective disorder (N=158) were randomly
assigned to 6 groups for 2 consecutive treatment periods, each 10 to 14 days.
Light treatment sequences were morning-evening, evening-morning, morning-morning,
and evening-evening (10,000 lux, 30 min/d). Ion density was 2.7 × 106
(high) or 1.0×104 (low) ions per cubic centimeter (high-high and low-low
sequences, 30 min/d in the morning).
Results: Analysis of depression scale percentage change scores showed low-density
ion response to be inferior to all other groups, with no other group differences.
Response to evening light was reduced when preceded by treatment with morning
light, the sole sequence effect. Stringent remission criteria, however, showed
significantly higher response to morning than evening light, regardless of
treatment sequence.
Conclusions: Bright light and high-density negative air ionization both appear
to act as specific antidepressants in patients with seasonal affective disorder.
Whether clinical improvement would be further enhanced by their use in combination,
or as adjuvants to medication, awaits investigation.
Arch Gen Psychiatry. 1998;55:875-882
The Studies of bright light therapy in the treatment of seasonal affective
disorder (SAD; also known as winter depression) in this issue of the ARCHIVES[1-3]
are sound studies that address important fundamental questions. Is bright
light therapy more than a placebo effect? Is morning bright light therapy
more effective than evening bright light?
IS BRIGHT LIGHT THERAPY MORE THAN A PLACEBO EFFECT?
Since bright light therapy was introduced as a treatment for SAD in the early
1980s, many have been concerned about the adequacy of the control conditions
used in the treatment studies. Bright light therapy poses a special problem
for blinding the patients to the active treatment: the patients see the bright
light box. During the 1980s, the usual placebo condition was a light box of
lower intensity, often of a different color. A pooled analysis of these data
showed that bright light is superior to dim light controls.[4] However, expectations
of the subjects sometimes predicted the clinical response. This placebo problem
is not unique to phototherapy. Antidepressant medication trials can be criticized
similarly for using inert pills as placebos; the relative lack of adverse
effects in the placebo group may weaken the expectations for the placebo conditions.[5]
Nonetheless, the question of the placebo effect clouded the interpretation
of bright light therapy efficacy studies.
Led by Eastman,[6] light therapy researchers began to address this problem.
Eastman et al[7] used a deactivated negative-ion generator as a placebo condition
and found its efficacy to be no different from the bright light therapy. Like
the bright light box, the negative-ion generator is a device, has a plausible
mechanism for efficacy, and requires the subject to sit beside it. In the
current study, Eastman et al[1] again used the deactivated negative-ion generator,
this time bolstering the placebo effect with an enthusiastic endorsement of
the device. Terman et al[2] followed up on this design and used high- and
low-dose negative-ion generators as comparison conditions. Both studies show
the superiority of bright light therapy over a plausible nonlight control
condition.
These positive results occurred despite other therapeutic aspects of placebo
response, such as ambient light exposure, that might confound studies of SAD.
In the placebo-controlled 5-week study of fluoxetine by Lam et al,[8] the
placebo responses markedly increased as the photoperiod increased. Rabkin
et al[9] found that even among patients with depression (not selected for
seasonality), the response rate to a 10-day administration of a placebo pill
was significantly less from November through February than during the rest
of the year. Terman et al[2] addressed this problem in their study by excluding
patients from analysis who did not relapse following the treatment trial.
In the Eastman et al[1] study in this issue, most of the subjects began the
4-week study in January and February and therefore were exposed to the increasing
photoperiod of late winter and early spring.
Direct sunshine even during short photoperiods may also be important. Patients
with SAD often report that they feel better on sunny days.[10] Because environmental
light exposure is difficult to control, SAD studies of efficacy may be analogous
to doing an efficacy study of Prozac with Prozac intermittently in the drinking
water. Changes in ambient light may explain some of the previous negative
studies of light therapy. In spite of this potential confound, both studies
in this issue found bright light superior to the placebo conditions.
IS MORNING BRIGHT LIGHT THERAPY MORE EFFECTIVE THAN EVENING BRIGHT LIGHT?
The 3 studies in this issue[1-3] are the largest studies to compare morning
and evening light therapy. Two studies support[2,3] and 1 partially supports[1]
the conclusion of most previous studies[4] that morning light is superior.
Some studies have found no significant difference.[11] No study has found
evening light superior to morning light. If morning and evening light are
equal in efficacy, one might expect a similar number of studies reporting
superiority of morning and evening light.
In addition to the placebo confounds cited earlier, there are several possible
reasons why some studies have not found differences between morning and evening
bright light therapy. Most studies have had small sample sizes. Diagnostic
heterogeneity among the patients with SAD could obscure real differences.
Some studies have found that the presence of hypersomnia[12] or atypical symptoms[13]
are good prognostic factors for response to morning bright light. The sample
of patients with SAD studied by Terman et al[2] had more atypical symptoms
than the sample of another study,[11] which did not show a difference. These
selective predictive factors also argue against light therapy merely being
a placebo response.[14]
Evening bright light can be considered a good "placebo." The light
apparatus and intensity are the same. Only the timing is different. Subjects
are almost always blind to the hypothesis of morning light superiority. Whether
one considers the evening light a placebo condition or simply a lower dose
of light treatment, evening light is probably a good control condition and
the superiority of the morning light strongly suggests that bright light therapy
is an active treatment.
The relative efficacy of morning and evening light is important for both practical
clinical and theoretical reasons. Morning light superiority over evening light
might be explained by the phase-shift hypothesis developed by Lewy et al.[15]
Many patients with SAD have phase-delayed circadian rhythms.[15,16,17] In
this issue, Lewy et al[3] present further data showing that morning bright
light phase-advanced the melatonin onset and was more efficacious than evening
bright light. If the phase-shift hypothesis is confirmed, clinicians might
need to individualize the timing of the bright light therapy: for example,
phase-advanced patients might benefit more from evening bright light.
CONCLUSION
The studies of Eastman et al[1] and Terman et al[2] provide good controls
and adequate sample sizes and, together with the previous studies of bright
light therapy, allow us to conclude that morning bright light therapy is effective
in treating SAD. All 3 studies add to the literature suggesting that morning
bright light is superior to evening bright light, a good control condition.
Together, the placebo-controlled studies and the morning-vs-evening studies
strongly support the efficacy of morning bright light in the treatment of
SAD and help establish bright light therapy as a first-line treatment for
SAD. Light therapy and SAD investigators may now turn their attention to other
research questions. Does the phase-shift hypothesis explain the superiority
of morning light over evening light? Is dawn simulation[18] effective in treating
SAD? Is light therapy effective in other disorders[19] such as subsyndromal
SAD, nonseasonal depression, premenstrual depression, circadian sleep-phase
disorders, sleep-maintenance insomnia, jet lag, and problems resulting from
shift work? In addition, the provocative finding by Terman et al[2] that exposure
to high-density negative ions has antidepressant effects in SAD calls for
replication and, if replicated, an exploration of possible mechanisms of action.
All these future studies will require continued careful attention to potential
placebo effects.
David H. Avery, MD
Harborview Medical Center
Box 359896
Department of Psychiatry and Behavioral Sciences
University of Washington School of Medicine
325 Ninth Ave
Seattle, WA 98104-2499
References
1. Eastman CI, Young MA, Fogg LF, Liu L, Meaden PM. Bright light treatment
of winter depression: a placebo-controlled trial. Arch Gen Psychiatry. 1998;55:883-889.
2. Terman M, Terman JS, Ross DC. A controlled trial of timed bright light
and negative air ionization for treatment of winter depression. Arch Gen Psychiatry.
1998;55:875-882.
3. Lewy AJ, Bauer VK, Cutler NL, Sack RL, Ahmed S, Thomas KH, Blood ML, Latham
Jackson JM. Morning vs evening light treatment of patients with winter depression.
Arch Gen Psychiatry. 1998;55:890-896.
4. Terman M, Terman J, Quitkin F, McGrath P, Stewart J, Rafferty B. Light
therapy for seasonal affective disorder: a review of efficacy. Neuropsychopharmacology.
1989;2:1-22.
5. Fisher S, Greenberg RP. How sound is the double-blind design for evaluating
psychotropic drugs? J Nerv Ment Disord. 1993;181:345-350.
6. Eastman CI. What the placebo literature can tell us about light therapy
for SAD. Psychopharmacol Bull. 1990;26:495-504.
7. Eastman CI, Lahmeyer HW, Watell LG, Good GD, Young MA. A placebo-controlled
trial of light treatment for winter depression. J Affect Disord. 1992;26:211-222.
8. Lam RW, Gorman CP, Michalon M, Steiner M, Levitt AJ, Corral MR, Watson
GD, Morehouse RL, Tam W, Joffe RT. Multicenter, placebo-controlled study of
fluoxetine in seasonal affective disorder. Am J Psychiatry. 1995;152:1765-1770.
9. Rabkin JG, Stewart JW, McGrath PJ, Markowitz JS, Harrison W, Quitkin FM.
Baseline characteristics of 10-day placebo washout responders in antidepressant
trials. Psychiatry Res. 1987;21:9-22.
10. Albert PS, Rosen LN, Alexander JR, Rosenthal NE. The effect of daily variation
in weather and sleep on seasonal affective disorder. Psychiatry Res. 1990;36:51-63.
11. Wirz-Justice A, Graw P, Krauchi K, Gisin B, Jochum A, Arendt J, Fisch
H, Buddeberg C, Poldinger W. Light therapy in seasonal affective disorder
is independent of time of day or circadian phase. Arch Gen Psychiatry. 1993;50:929-937.
12. Terman M, Amira L, Terman JS. Predictors of response and nonresponse to
light treatment for winter depression. Am J Psychiatry. 1996;153:1423-1429.
13. Avery DH, Khan A, Dager SR, Cohen S, Cox GB, Dunner DL. Morning or evening
bright light treatment of winter depression? the significance of hypersomnia.
Biol Psychiatry. 1991;29:117-126.
14. Terman M. Problems and prospects for use of bright light as a therapeutic
intervention. In: Wetterberg L, ed. Light and Biological Rhythms in Man. Stockholm,
Sweden: Pergamon Press; 1993:421-437.
15. Lewy AJ, Sack RL, Miller S, Hoban TM. Antidepressant and circadian phaseshifting
effects of light. Science. 1987;235:352-354.
16. Sack RL, Lewy AJ, White DM, Singer CM, Fireman MJ, Vandiver R. Morning
vs evening light treatment for winter depression: evidence that the therapeutic
effects of light are mediated by circadian phase shifts. Arch Gen Psychiatry.
1990;47:343-351.
17. Avery DH, Dahl K, Savage MV, Brengelmann GL, Larsen LH, Kenny MA, Eder
DN, Vitiello MV, Prinz PN. Circadian temperature and cortisol rhythms during
a constant routine are phase-delayed in hypersomnic winter depression. Biol
Psychiatry. 1997;41:1109-1123.
18. Avery DH, Bolte MA, Wolfson JK, Kazaras AL. Dawn simulation compared with
a dim red signal in the treatment of winter depression. Biol Psychiatry. 1994;36:181-188.
19. Lam RW, ed. Seasonal Affective Disorder and Beyond. Washington, DC: American
Psychiatric Press; 1998.
(Arch Gen Psychiatry. 1998;55:863-864)
Light is the first treatment in psychiatry to evolve directly out of modern neuroscience. Yet paradoxically, the biological psychiatry establishment has regarded light therapy with a certain disdain and relegated it to the edge of the paradigm—not molecular enough, a bit too Californian-alternative, a bit too media overexposed, merely a placebo response by mildly neurotic middle-aged women who don't like nasty drugs.
But light is as effective as drugs, perhaps more so. Three articles in this
issue provide the best evidence to date that light is an effective antidepressant
in seasonal affective disorder (SAD).[1-3] Placebo response[4] and nonspecific
factors[5] are an issue in all clinical trials: for light therapy, "blindness"
is not simply an oxymoron. Many psychiatrists are unaware that the advantage
of antidepressant drugs over placebo in controlled trials is so small that
only multicenter studies can answer questions of relevance.[4,6,7] That 2
single centers[1,2] in large, controlled, blind trials are able to show that
light therapy works better than a convincing placebo is therefore extremely
important.
The idea of light therapy came from research into mammalian seasonality, where
changes in sleep, eating behavior, and weight, for example, are exquisitely
tuned, for each species, to day length at the latitude inhabited.[8] The circadian
pacemaker in the suprachiasmatic nuclei acts as a "clock for all seasons":
the window of responsivity to light at dawn and dusk is dependent on prior
photoperiod.[9] Humans too have retained their intrinsic seasonal responses,[10]
though these are mostly masked by splendid isolation in living boxes where
lighting and temperature are manipulated at will. Indeed, such "unnatural"
behavior may be one of the factors precipitating seasonal mood decline in
vulnerable individuals.
In the 15 years since the pioneer National Institute of Mental Health study
describing SAD and its treatment by bright light,[11] a remarkable research
interest has developed worldwide, not only in the dark northern fastnesses
of Alaska, Canada, Scandinavia, and Siberia, but also in India, Italy, Japan,
and the inverse winter of the southern hemisphere. Light therapy is widely
used, in spite of the skepticism of colleagues who do not "believe"
in a syndrome they have never seen (only about 10% of patients with SAD have
ever been hospitalized[8]). Since many study patients are recruited via newspaper
advertisements, these psychiatrists consider them merely high placebo responders.
The new evidence indicates that they are not.
New York, NY, at 41°N, Chicago, Ill, at 42°N, and Portland, Ore, at
45°N: these 3 articles,[1-3] with the largest numbers so far in individual
studies, scan the United States from east to west at around the same northerly
latitude. In spite of the differences in design, some important correspondences
emerge with respect to remission rates (Table).
The 2 placebo-controlled trials[1,2] (what a very cunning idea that negative-ion
generator was!) have nearly identical results: both morning and evening light
are better than placebo, and morning light is superior to evening light. The
third study[3] also demonstrates a morning light superiority but has overall
lower improvement rates. In emphasizing the similarities—and not dissecting
out why certain differences are found between these populations, or in European
studies[12,13]—we have to be cognizant that these comparisons of therapeutic
outcome are based on very stringent criteria for remission, not just response,
within a rather short time (2-4 weeks). Such stringent criteria, when applied
to a 5-week multicenter trial of fluoxetine in patients with SAD, did not
differentiate between drug (33%, n=36) and placebo (28%, n=32).[14] Patients
with SAD treated with light for 5 weeks tended to remit more (50%, n=20) than
those treated with fluoxetine (25%, n=20; P=.10).[15]
The Society for Light Treatment and Biological Rhythms (www.websciences.org/sltbr/)
has played an important role in the last decade to establish guidelines, standards,
and consensus statements for light therapy. Light is now recommended as the
treatment of choice for SAD.[16,17] However, in spite of international recognition,
only in Switzerland has the additional economic argument that light is cheaper
than drugs attained government endorsement and mandatory reimbursement by
medical insurance. In addition to SAD, new applications for light have recently
been summarized in the Society for Light Treatment and Biological Rhythms
Task Force commissioned by the American Sleep Disorders Association: for circadian-related
sleep disorders, aging and Alzheimer's disease, jet lag, and shift work.[18]
But few psychiatrists have yet recognized that light therapy should be considered
a mainstream antidepressant modality. Seasonality of depression can also overlap
other diagnoses, such as chronic and intermittent depressions, rapid brief
depression, dysthymia, bulimia, premenstrual dysphoric disorder, etc. Long-term
follow-up documentation indicates that whereas some patients may flip in and
out of modes, most remain seasonally susceptible.[19] There is intriguing
preliminary evidence for light treatment beyond SAD.[20] Kripke has carried
out a systematic comparison of light and antidepressant drug studies in nonseasonal
major depression.[7] He argues that we should routinely prescribe light for
nonseasonal depression[7]—at least as a drug adjuvant—even before
waiting for results from large multicenter trials (which may not even begin,
since there is no industrial interest in them).
We need to separate 2 issues: clinical efficacy of light vs mechanisms of
action. These clinical trials[1-3] clearly support the claim that light is
antidepressant, rather than elucidating how it works. Interpretation of the
available data requires multiple levels of explanation. Light targets a neuroanatomical
region (the circadian clock), and the SAD literature provides experimental
support for both the "phase-shift hypothesis" and the "too-few-photons
hypothesis," rather than the original "photoperiod hypothesis."
Circadian and serotonergic hypotheses of the pathophysiological mechanisms
of SAD are not incompatible: light also acts on a neurochemical substrate
within that clock, the serotonergic input from the median raphe. Here we need
further research to tease out mechanisms.
The evidence is in that light is an active neurobiological agent. But light
therapy has little chance to be widely and properly used for a variety of
ills, as long as it appears to the policymakers and grant-givers to lie uncomfortably
between pharmaceutical company neglect (for obvious reasons) and the molecular
reductionism of academe. These attitudes strikingly contrast with patients'
acceptance of light therapy. Light therapy is easy to administer in outpatient
settings, lacks major side effects, and, importantly, is cost-effective. Whatever
its mode of action, it demands inclusion in the antidepressant armamentarium,
now.
Background: Although hypotheses about the therapeutic mechanism of action of light therapy have focused on serotonergic mechanisms, the potential role, if any, of catecholaminergic pathways has not been fully explored.
Methods: Sixteen patients with seasonal affective disorder who had responded
to a standard regimen of daily 10,000-lux light therapy were enrolled in a
double-blind, placebo-controlled, randomized crossover study. We compared
the effects of tryptophan depletion with catecholamine depletion and sham
depletion. Ingestion of a tryptophan-free amino acid beverage plus amino acid
capsules was used to deplete tryptophan. Administration of the tyrosine hydroxylase
inhibitor -methyl-para-tyrosine was used to deplete catecholamines. Diphenhydramine
hydrochloride was used as an active placebo during sham depletion. The effects
of these interventions were evaluated with measures of depression, plasma
tryptophan levels, and plasma catecholamine metabolites.
Results: Tryptophan depletion significantly decreased plasma total and free
tryptophan levels. Catecholamine depletion significantly decreased plasma
3-methoxy-4-hydroxyphenylethyleneglycol and homovanillic acid levels. Both
tryptophan depletion and catecholamine depletion, compared with sham depletion,
induced a robust increase (P<.001, repeated-measures analysis of variance)
in depressive symptoms as measured with the Hamilton Depression Rating Scale,
Seasonal Affective Disorder Version.
Conclusions: The beneficial effects of light therapy in the treatment of seasonal
affective disorder are reversed by both tryptophan depletion and catecholamine
depletion. These findings confirm previous work showing that serotonin plays
an important role in the mechanism of action of light therapy and provide
new evidence that brain catecholaminergic systems may also be involved.
Arch Gen Psychiatry. 1998;55:524-530
Alexander Neumeister, MD; Nicole Praschak-Rieder, MD; Barbara Heßelmann,
MD; Marie-Luise Rao, PhD; Judith Glück, Msc; Siegfried Kasper, MD
Background: A dysfunction of the serotonin system may play a major role in
the pathogenesis of seasonal affective disorder. Bright light therapy has
been shown to be effective in the treatment of winter depression in patients
with seasonal affective disorder. Light therapy-induced remission from depression
may be associated with changes in brain serotonin function.
Methods: After at least 2 weeks of clinical remission, 12 drug-free patients
who had had depression with seasonal affective disorder underwent tryptophan
depletion in a double-blind, placebo-controlled, balanced crossover design
study.
Results: Short-term tryptophan depletion induced a significant decrease in
plasma free and total tryptophan levels (P<.001 for both, repeated measures
analysis of variance), with peak effects occurring 5 hours after ingestion
of a tryptophan-free amino acid drink. It emerged that tryptophan depletion
leads to a transient depressive relapse, which was most pronounced on the
day after the tryptophan-depletion testing. No clinically relevant mood changes
were observed in the control testing.
Conclusions: The maintenance of light therapy-induced remission from depression
in patients with seasonal mood cycles seems to depend on the functional integrity
of the brain serotonin system. Our results suggest that the serotonin system
might be involved in the mechanism of action of light therapy.
Abstract
Clinical symptoms and response to light therapy treatment are important
factors for the definition of seasonal affective disorder (SAD) as a subgroup
of major depression. As part of a study on 39 depressive outpatients who underwent
a two-week course of light therapy, we attempted to strengthen the definition
of SAD with biological markers such as auditory evoked potentials (AEP).
According to the changes in their Hamilton depression scores over the course
of therapy, patients were classified into three response groups: (1) The nonresponder
group with no or marginal improvement, (2) the intermediate group with only
a temporary improvement and (3) the responder group with an overall improvement.
Clinically, patients with SAD symptoms showed a significantly better response
to light therapy. Electrophysiologically, the responder group showed a smaller
P300 amplitude before and during treatment compared with both other groups,
as did the SAD compared with the non-SAD patients. Additionally, patients
under antidepressant medication had a reduced P300 amplitude in contrast to
the drug-free patients.
Our conclusion is that the amplitude of P300 as a biological trait marker
supports the classification of SAD as a subgroup of depression and suggests
that the pathophysiological basis varies among the subtypes of affective disorder.
(German J Psychiatry 1998;1:41-52)
Key Words: light therapy, phototherapy, seasonal affective disorder, depression,
P300, event-related potentials
Introduction
As first described by Rosenthal et al. (1984), 'the diagnosis of seasonal
affective disorder (SAD) - a recurrent major depression in autumn and winter
remitting in spring and summer - has been operationalised and incorporated
into the Diagnostic and Statistical Manual of Mental Disorders, DSM-III-R
(American Psychiatric Association 1987)' (Wirz-Justice 1993). Light therapy
as a natural treatment was developed on the basis of circadian rhythm research.
The antidepressant effect of this therapy has been well established (e.g.
Terman et al. 1989, Tam et al. 1995), despite the extent of a placebo component
as discussed by Eastman et al. (1990, 1992). However, hypotheses about the
physiological basis of SAD and the different assessments of light therapies
(light intensities, duration and time of day of treatment) are the subject
of controversial discussion.
SAD can be defined as a subgroup of major depression from the diagnostic and
clinical points of view. The finding of biological parameters such as electroencephalographic
(EEG) differences would strengthen this definition. P300, a positive event-related
potential (ERP) component of the EEG, reflects attentional and decision processes.
It peaks around 300 ms after the occurrence of a rare stimulus and is well
established in psychiatric research. Several studies have shown a reduced
amplitude of the auditory evoked P300 in depressive patients compared with
healthy controls, e.g. Roth et al. (1981), Blackwood et al. (1987) and Gangadhar
et al. (1993). Pfefferbaum et al. (1984) found reduced amplitudes of auditory
and visual evoked P300 only in drug-free patients. Maurer and Dierks (1988)
and Sara et al. (1994) observed only nonsignificantly reduced P300 amplitudes
in depressive patients compared with controls. As a possible explanation for
their results, Sara et al. mention the heterogeneity of groups of depressive
patients classified using DSM-III criteria and that P300 abnormalities may
be related only to a specific aspect of the depressive syndrome.
This interpretation is supported by studies on subgroups of depressive patients.
Pholien et al. (1987) found reduced amplitudes in melancholic compared with
nonmelancholic depressive patients (DSM III classification) and intermediate
amplitudes in a dysthymic group, although all groups of patients showed reduced
amplitudes compared with controls. Santosh et al. (1994) investigated patients
with a DSM III-R melancholic depression and found a reduced P300 in those
subjects who had additional psychotic features. Hansenne et al. (1994) found
reduced P300 amplitudes in depressive patients who had attempted suicide compared
with patients who had not attempted suicide.
In SAD patients, Murphy et al. (1993) found no differences in visual evoked
potentials (N1, P2, N2, P300) compared with controls. Duncan et al. (1990)
described an increase of visual P300 amplitude in SAD patients during the
assessment of a light therapy course with a correlation between P300 changes
and the improvement in psychopathology. Auditory P300 was not affected by
light therapy treatment in that study.
In the present study we measured the auditory P300 before and during a course
of light therapy on depressive patients. The finding of group differences
or changes during therapy will give more emphasis for the definition of SAD
as a subgroup of major depression and suggest a different pathophysiological
base of SAD. Additionally, differences in ERP will be of clinical importance
as predictive variables for the assessment of different therapies.
Because the therapeutic efficacy of the light intensity used is still a matter
of dispute (e.g. Wirz-Justice 1993), we chose a cross-over design with two
different light intensities to confirm intensity-dependent responses in light
therapy.
Material and Methods
The study included 39 depressive out-patients (30 female, 9 male) who fulfilled
the DSM III-R criteria for major depressive disorder (296.32: n = 38; 296.31:
n = 1) and had a minimum score of 13 on the 21-item Hamilton Depression Rating
Scale (Hamilton 1967) before therapy. Thirty patients showed a seasonal pattern
of depression. Twenty-two of them fulfilled all 4 items, 8 fulfilled 2 or
3 items of the DSM III-R criteria for an SAD diagnosis. Nine patients had
no seasonal symptoms. The mean age was 48 years (SD 10.6). Twenty-three patients
were drug free, 16 patients were treated with antidepressant medication before
and during therapy (nine of them with antidepressants only, two with antidepressants
and neuroleptics, three with antidepressants and lithium, one with lithium
only, one with a tranquilliser only). The last changes in medication were
made at least two weeks before the start of light therapy.
Light therapy was performed for two hours daily in the early evening for a
period of two weeks between November and February. To test therapeutic efficacy
in relation to light intensity, a cross-over design was devised. Patients
were divided into two groups: Group 1 received full-spectrum fluorescent light
(Theralux ATL-6) with an intensity of 2500 lux for the first week and 300
lux for the second week, group 2 received the inverse light-intensity pattern.
The patients sat at a distance of 1 m from the light source (2500 lux treatment)
and were instructed to look periodically into it. For the 300 lux treatment,
the lights were dimmed and the distance increased to 3 m.
Before therapy (day 1), after week one (day 8) and after week two (day 15),
Hamilton depression scores were measured in the morning and evening by the
same qualified investigator.
Therapy response was defined as the relative change in the Hamilton depression
score during the two-week light therapy course, based on the mean of morning
and evening scores. Response was calculated as follows: Response [%] of day
d = 100 * (Hamilton day 1 - Hamilton day d) / Hamilton day 1 (where d = 8
or 15 respectively).
The electrophysiological recordings were performed in the late morning. Nineteen
gold electrodes were placed according to the international 10-20 system, all
referred to linked mastoids. Vertical and horizontal eye movements were recorded
with two electrodes supra-/infraorbitally and two electrodes at the outer
canthal positions. Impedances were below 5 kOhm. P300 was generated with randomised
stimuli: A frequent 1000 Hz tone with an occurrence of 80 % and a 2000 Hz
tone (target) with a 20 % occurrence. Duration of the tones was 50 ms including
10 ms rise and fall. The interstimulus interval was 1.5 s, digitation rate
was 256 Hz. Data were filtered online with a 0.1 Hz to 70 Hz bandpass. The
task was to count the target tone silently. To assure that the subjects performed
the task correctly, the number of targets was changed between sessions from
30 to 41.
Data processing: Eye movements and eye blinks were corrected using the regression
method of Anderer et al. (1989a). A prestimulus interval of 200 ms was used
for baseline correction. Data were controlled manually, only artifact-free
trials were included in further analysis. The averaged waveforms were lowpass
filtered with 16 Hz. The largest positive deflection in the time range from
250 to 500 ms was defined as the P300 peak. Some data sets showed no clear
P300 pattern at peripheral electrode sites. Therefore, only the nine electrodes
with the best P300 pattern were included in further analysis (F4, Fz, F3,
C4, Cz, C3, P4, Pz, P3). Statistical tests were performed with MANOVAs, for
data of nominal scale level the Chi2-test was used.
Results
According to the different variables, we subdivided clinical and ERP results
into light-intensity pattern, response group definition, SAD symptoms and
antidepressant medication.
Clinical data
To examine the influence of light intensity on therapy response, a MANOVA
with the two independent factors light-intensity pattern and SAD symptoms
and Hamilton depression score as a dependent factor (repeated measuring for
day 1, 8 and 15) was computed. The hypothesised higher efficacy of the 2500
lux light intensity should have shown different Hamilton depression scores
at day 8 and probably at day 15 in both treatment groups. However, there were
no significant interactions which would confirm our hypothesis:
Light intensity pattern * day: F(2, 70) = 1.85, p = 0.16 (Table 1).
Light intensity pattern * SAD symptoms * day: F(2, 70) = 0.83, p = 0.44.
Table 1: Means and standard deviations of Hamilton depression scores for the
two light-intensity pattern groups (first week/second week).
day 1 day 8 day 15
300/2500 lux (n=23) 19.2 (4.3) 11.8 (6.3) 9.5 (6.9)
2500/300 lux (n=16) 19.4 (6.1) 12.1 (7.1) 12.2 (8.6)
Two different definitions of response groups where made post-hoc because no
influence of light intensity on therapy response could be seen.
The first response group definition was made due to the fact that there were
considerable changes in Hamilton depression scores between day 8 and day 15.
To represent the time course of therapy, we defined three groups (Table 2).
Patients were defined as (1) nonresponders when their improvement (decrease
in Hamilton depression score) was less than 25 % at day 8 and/or day 15 (n
= 8). This 25 % cut-off was previously used by Nagayama et al. (1991). The
patients with a Hamilton depression score decrease of 25 % or more at day
8 and/or day 15 were defined as (2) responders as long as their score at day
15 was lower than or equal to that at day 8 (n = 21). The intermediate group
(3) consisted of those patients whose Hamilton depression scores decreased
(25 % or more) from day 1 to day 8 but increased again from day 8 to day 15
(n = 10).
There were no significant differences in day 1 Hamilton depression scores
between the three groups and no differences in terms of age, gender or medication
(Tables 3 and 4).
Secondly, a 'classical' two-group definition was made according to Terman
et al. (1989). The cut-off for grouping patients as responders (n = 16) or
nonresponders (n = 23) was a 50 % decrease in Hamilton depression score from
day 1 to day 15. When comparing the two group definitions, 15 subjects of
the responder and one of the intermediate group were 'Terman-responders'.
Table 2: Group means and standard deviations of Hamilton depression scores.
day 1 day 8 day 15
Responder group (n=21) 18.2 (4.6) 9.5 (5.3) 5.2 (4.3)
Intermediate group (n=10) 19.5 (4.3) 10.2 (4.1) 14.8 (4.7)
Nonresponder group (n=8) 22.2 (6.5) 20.3 (5.5) 19.4 (6.1)
Table 3: Distribution of gender and age among response groups.
Mean age (SD) female male
Responder group 49.1 (10.4) 16 5
Intermediate group 46.9 (10.8) 8 2
Nonresponder group
46.5 (11.9)
6
2
Table 4: Classification of patients with or without psychotropic drugs in
the three therapy response groups and in groups with or without SAD symptoms.
Drug-free Antidepressants Antidepressants + Neuroleptics Antidepressants
+ Lithium Lithium Tranquilliser
Responder group 10 5 2 3 0 1
Intermediate group 8 2 0 0 0 0
Nonresponder group 5 2 0 0 1 0
SAD 20 5 1 3 0 1
non-SAD 3 4 1 0 1 0
The patients with SAD symptoms had lower day 1 Hamilton depression scores
than the non-SAD patients (17.9 vs. 23.7; SD 4.5/4.7) and a significantly
better response to light therapy: day 1 to day 8: 44.4 % (SD 27.2) vs. 20.8
% (17); day 1 to day 15: 51.2 % (31.1) vs. 29.5 % (35.5); main effect for
SAD group: F[1, 37] = 5.3, p = 0.027. Eighteen of 21 patients of the responder
group, 8 of 10 patients of the intermediate group and 4 of 8 patients of the
nonresponder group showed SAD symptoms.
The groups of patients with different antidepressant medication presented
no significant differences in day 1 Hamilton depression scores or in therapy
response.
ERP data
All subjects performed the task well. For day 1, ERP data of all 39 patients
could be included in this analysis. The day 8 data set of one patient had
to be excluded due to artifacts, while an EEG could not be recorded for another
patient at day 15. So the complete sample consisted of the data of 37 subjects.
For statistical analysis, MANOVAs were computed with P300 amplitudes (or latencies
respectively) as a dependent variable for each electrode site and day of recording
(repeated measures factors). The independent variables are specified below.
Due to the different sample sizes, MANOVAS were computed additionally for
day 1 only for the variables response group, SAD symptoms and medication.
For pairwise post-hoc comparisons, Fisher's-LSD test was used.
According to the clinical results, the light intensity pattern (as an independent
variable) showed no influence on P300.
The comparison of the three response groups showed lower P300 amplitudes in
the responder group in contrast to the intermediate and nonresponder groups.
(Table 5). The MANOVA with the two independent variables response group and
light-intensity pattern revealed significant main effects for response group:
F(2, 31) = 3.8; p = 0.035 and electrode site: F(8, 248) = 37.4, p < 0.001.
Post-hoc comparisons showed significantly lower amplitudes in the responder
group compared with the nonresponder group (p = 0.01). The comparison between
responder and intermediate group failed to reach significance (p = 0.13).
Nonresponder and intermediate group did not differ from each other. There
was no main effect for the day of recording and no interactions between any
of these 4 variables.
A MANOVA for day 1 only, with all 39 subjects included, revealed this main
effect for response group: F(2, 36) = 4.31, p = 0.021, where post-hoc comparisons
showed lower amplitudes between the responder group and the nonresponder group
(p = 0.033) and the intermediate group (p = 0.093), respectively.
The effect of antidepressant medication illustrated below did not affect these
results, due to the distribution of subjects with or without medication in
the three response groups (Chi-Square = 10.3; p = 0.41; n = 39; cf. Table
4).
To compare these results with the response group definition after Terman et
al., a MANOVA was computed which showed nearly significantly lower P300 amplitudes
in the better responding patients. Main effect group: F(1, 35) = 3.9, p =
0.056.
Table 5: Group means of P300 amplitudes before light therapy (day 1). R -
Responder group, I - Intermediate group, N - Nonresponder group.
Elektrode site
R (n = 21) I (n = 10) N (n = 8)
The comparison between the groups of patients with or without SAD symptoms
showed lower P300 amplitudes in the SAD group at frontal and central electrodes
(Table 6). A MANOVA with the SAD group as the independent factor yielded only
trends for a group * electrode interaction: F(8, 280) = 1.7, p = 0.097, and
for a group * electrode * day interaction: F(16, 560) = 1.5, p = 0.095. For
day 1 there was also only a trend towards a group * electrode interaction:
F(8, 296) = 1.75, p = 0.087. It should be noted that these results were probably
masked by the effect of treatment with antidepressant medication shown below
(67 % of the SAD patients were drug free but only 42 % of the non-SAD patients,
cf. Table 4).
Table 6: Group means of P300 amplitudes before light therapy (day 1). Patients
with vs. patients without SAD symptoms.
Electrode site
SAD (n = 30) non-SAD (n = 9)
Additionally, this study revealed an influence of treatment with antidepressant
medication on P300 amplitude. The drug-free patients had larger amplitudes
than the other patients. When dividing medication into several classes (Table
7), we found a main effect with F(5, 33) = 2.66, p = 0.04 (day 1 only). For
day 1, 8 and 15 we found a medication group * electrode-site interaction with
F(24, 248) = 1.61, p = 0.039. Post-hoc comparisons for both MANOVAs showed
significant differences for all electrodes between the drug-free group (n
= 23) and the antidepressant-only group (n = 9 for day 1 only, n = 7 for all
three recordings).
For P300 latency no statistical difference could be found.
Age and gender of patients showed no influence on P300 amplitude.
Table 7: Means of P300 amplitudes of medication treatment groups before therapy.
Electrode site
Drug-free (n=23) Antidepressants (n=9) Antidepressants + Neuroleptics (n=2)
Antidepressants + Lithium (n=3)
F Discussion
Thirty-nine depressive patients took part in our two-week light therapy study.
The 30 patients with SAD symptoms showed a significantly better response to
the therapy than the others. The result that some of the SAD patients did
not respond to light therapy is in line with other studies (Duncan et al.
1990; review in Murphy et al. 1993). Concerning the applied light intensity
pattern, we found no differences in therapy response between 300 or 2500 lux
intensities. The light intensity which is necessary for successful therapy
is still not yet clear and is a matter of controversy in the literature (reviewed
in Wirz-Justice 1993). Perhaps there are methodological aspects to be considered,
such as natural light exposure. To determine the light intensities used for
a successful therapy it is necessary to measure the actual light intensity
reaching the retina during treatment sessions, as mentioned by Wirz-Justice
(1993), plus the natural light exposure.
We defined three response groups to represent the course of changes in psychopathology.
Because this definition was made post-hoc, we compared it with a classical
two-groups design, grouping patients according to their psychopathological
states at the end of therapy.
The ERP results showed an overall (day 1, 8, 15) reduced P300 amplitude in
the responder group compared with the intermediate and the nonresponder group
(and in the responders compared with the nonresponders of the two-group design).
P300 divided the responders from both the other groups before therapy, while
the psychopathological states were equal. P300 changes did not occur over
the course of therapy. Although the neurophysiological basis of P300 generation
is still not yet clearly understood (Charles and Hansenne 1992, Polich and
Kok 1995), our results point to a biological difference in depressive patients
who do or do not respond to light therapy.
The P300 amplitudes of the intermediate group did not differ from those of
the nonresponder group. This finding may imply a similar physiological basis
of the disorder in the patients of both groups. Therefore the only temporary
response to light therapy of the intermediate group might be due to a placebo
and not to a physiological effect of light therapy.
It has to be noted that the intermediate group was not equal in terms of medication
treatment compared to the two other groups. Only 2 patients received antidepressants,
the other 8 patients were drug free. The effect of medication treatment might
have shifted P300 amplitude in this group to higher values relative to the
others, even though the interaction was not statistically significant.
The results of our study lead us to the conclusion that the biological trait
marker P300 amplitude strengthens the definition of a subgroup of depressive
patients which consists of light therapy responders. The results were not
so clear when the patients were grouped according to seasonal symptoms instead
of response to light therapy, which might be due to a masking effect of medication
treatment. But it seems to be obvious that the diagnostic criteria SAD symptoms
and the clinical criteria therapy response are not independent factors, but
are strongly related to each other.
Although group differences became quite clear, there is too much variance
between and within the response groups to use the P300 amplitude of a single
measure for predicting the success of light therapy treatment.
Acknowledgements
We wish to thank Kerstin Herwig and Ute Klein for their skilful acquisition
of EEG data and Daniela Roesch-Ely for discussing and proof-reading the draft
of this paper.
by Alfred J. Lewy, MD, PhD
Published in Psychiatric Annals 17:10 October 1987
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 AM i s 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 AM 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
later time.
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 cues (zeitgebers), particularly the
24-hour light-dark cy cle. 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 RYHTHMS
Until recently, chronobiologists 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 r adically, 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, whi ch 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 Wever,4 Eastman,5 and Czeisler,6 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 Eastman.8 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 circadian r hythms.
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 light.9 This patient had a 13-year history
of winter depression that remitted spontaneously in the spring. Our first
approach was to lengt hen 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 f or cueing biological rhythms.)
Following the first successful treatment, nine patients were treated the next
year with bright light and dim light exposure at these times.10 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 animals.11 PRCs are empirically
derived from ex periments in which animals free-run in constant dark and are
briefly exposed to light pulses.12-15 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 lat er 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, the re 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 pra ctice, 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 AM. 16,17 We measured their plasma
melatonin levels the first day and then advanced dusk from about 9PM to 4PM
by having them avoid bri ght 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 remaine d 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 interpet the end-of-the-week advance in
both the onset and the offset of melatonin production as a result of removin
g 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 hypothesized PRC.
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 ma y 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 phy siological 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 t he morning advances circadian rhythms.18-20
DIAGNOSING ADVANCED OR DELAYED CIRCADIAN RHYTHMS IN DEPRESSED PATIENTS
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.
Previous psychiatric 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 night,23 was at
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 d isturbance,
in which sleep is not as delayed as the other circadian rhythms.
SLEEP AS A MARKER FOR DIAGNOSING ADVANCED OR DELAYED CIRCADIAN RHYTHMS
The most accessible, and therefore clinically useful, marker for circadian
phase type may be sleep (sleep offset is more reliable than sleep onselt).
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 tu rn, 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 o n the
perceived light-dark cycle.21,24
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 reached).24
Sleep is del ayed 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 timing.26 In a study done a few years ago, we showed that the optimum
wavelengths for mel atonin suppression are around 509 nm.27 This wavelenth
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 affecti ve 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 mechani sm of action should: 1) Optimize the antidepressant
efficacy of light treatment, 2) Control sleep time and bright light exposre
around dawn and dusk, and 3) 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 DEPRESSION)
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 morn ing 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 AM 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 thrd 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 evening.
The patients 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 ev ening 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 wo uld 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 p hase 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 tempe rature and cortisol, are affected by 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. Mornin g 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 each other.
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 exposure). On average,
the two light exposures had the same ant idepressant 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 hypothe sized 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 normal
controls.
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 d uring 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 betw een 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 symp toms.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
sle ep (holding their circadian rhytms constant). Guidelines for the practical
treatment of patients with seasonal affective disorder are provided in the
Figure.
CONCLUSION
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 identifi cation of useful circadian phase markers that
might help to phase type patients. Either baseline time of 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 effe cts 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*
1. If patients do not have early morning awakening, schedule 1-2 hours of
2500 lux exposure immediately upon awakening. (Editor's Note: Studies have
shown that 10,000 lux can reduce this time to 1/2 hour.)
2. If patients begin treatment on the weekend, they may not have to arise
earlier to accommodate the morning light exposure; early rising may retard
the response for a few days.
3. The response begins 2-4 days after beginning light therapy and is usually
complete within 2 weeks.
4. These patients should minimize any advance in their sleep time and should
avoid bright light in the evening.
5. If patients do not respond to treatment, they may need a longer duration
of morning light.
6. If patients respond only transiently or begin to complain of early morning
awakening or severe fatigue in the evening, they may be becoming overly phase
advanced due to too much morning light. The duration of morning should be
reduced but still be gun immediately upon awakening or some late evening light
exposure could be added.
7. Some patients may respond to an immediate "energizing" effect
of bright light exposure (this may be a placebo effect), which if not administered
too late in the evening might be helpful.
8. Once a response has been achieved, the duration and frequency of light
exposures can be reduced. Always begin light exposure immediately upon awakening
or a little later if patients become overly phase advanced.
9. If there is still no response, a trial of evening bright light (7-9 PM)
may be necessary. These patients should minimize any delay in their sleep
time and should avoid bright light in the morning.
10. Appropriate precautions should be taken to avoid any possibility of eye
discomfort or injury (eg, an eye history and exam if indicated, instructions
never to stare at the sun, use of safe articial light sources, recommendation
of follow-up check-up s).
These guidelines can be applied in the treatment of delayed and advanced sleep
phase syndromes, with the modification that sleep is held constant only after
it achieves a normal phase position. In the treatment of phase advanced sleep
or mood disorders, evening bright light should be used and bright light should
be avoided in the morning.
Received: 28 May 1996 / Final version: 6 May 1997
Abstract Mood changes synchronised to the seasons
exist on a continuum between individuals, with anxiety
and depression increasing during the winter
months. An extreme form of seasonality is manifested
as the clinical syndrome of seasonal a§ective disorder
(SAD) with carbohydrate craving, hypersomnia,
lethargy, and changes in circadian rhythms also evident.
It has been suggested that seasonality and the
symptoms of SAD may be due to changing levels of
vitamin D3, the hormone of sunlight, leading to
changes in brain serotonin. Forty-four healthy subjects
were given 400 IU, 800 IU, or no vitamin D3 for 5 days
during late winter in a random double-blind study.
Results on a self-report measure showed that vitamin
D3 significantly enhanced positive a§ect and there was
some evidence of a reduction in negative a§ect. Results
are discussed in terms of their implications for
seasonality, SAD, serotonin, food preference, sleep, and
circadian rhythms.
Key words Seasonality · Seasonal a§ective disorder ·
Vitamin D3 · Serotonin · Circadian rhythms
Introduction
Increased levels of anxiety and depression during winter
months occur in the normal population and appears
to be related to the shortened photoperiod and lower
light levels (Schlager et al. 1993). This seasonality exists
on a continuum between individuals from no change
across the seasons to its extreme form in the syndrome
of seasonal a§ective disorder (SAD or ìwinter depressionî)
(Spoont et al. 1991). In SAD, symptoms of
sadness, irritability, anxiety, lethargy, increased
appetite, carbohydrate craving, and hypersomnia occur
in autumn/winter and alternate with remission or
hypomania in spring/summer (Rosenthal et al. 1984).
Over 80% of SAD su§erers are women, age at onset is
typically in the third decade of life, and both incidence
and length of depression increase with latitude
(Rosenthal et al. 1985; Rosenthal and Wehr 1987).
Phototherapy using broad spectrum bright artificial
lights (> 2500 lux) has been demonstrated to be
e§ective in the treatment of SAD, with relief from
symptoms occurring within several days (Rosenthal
et al. 1984). The mechanism by which phototherapy
exerts its potent therapeutic e§ects is still not yet fully
understood and there is disagreement as to the optimal
time of day for the administration of treatment
(Avery and Dahl 1993).
Several hypotheses have been put forward to explain
seasonality (Avery and Dahl 1993), including disrupted
circadian rhythms, phase delayed circadian rhythms,
and low melatonin. Low serotonin (5-HT) has been
linked to the symptoms of SAD (Wurtman and
Wurtman 1989), and it has been suggested by Stumpf
and Privette (1989) that vitamin D3, the hormone of
sunlight, may play a role in seasonal cycles of mood
due to regulation of 5-HT. To date, the psychological
e§ects of vitamin D3 and its implications for seasonal
rhythms in mood are yet to be investigated.
Vitamin D3 is a steroid synthesised in the skin by
conversion from 7-dehydrocholesterol in response to
ultraviolet B radiation and subsequently undergoes
hydroxylations in liver and kidney to become the active
hormone 1,25-dihydroxyvitamin D3 (DeLuca 1979).
Since 1,25-dihydroxyvitamin D3 is a hormone rather
than a vitamin, Stumpf and Privette (1989) suggested
the use of the term ìsoltriolî, meaning ìhormone of
sunlightî, to be consistent with other hormone terminology.
The renal hydroxylation is subject to regulation
by other hormones including triiodothyronine
(DeLuca 1979), oestrogen (Tanaka et al. 1976), insulin
A.T.G. Lansdowne · S.C. Provost (*)
Department of Psychology, The University of Newcastle,
University Drive, Callaghan NSW 2308, Australia
e-mail : provost@psychology.newcastle.edu.au
(Levin et al. 1976), and prolactin (Spanos et al. 1976).
Soltriol regulates whole body calcium levels by promotion
of intestinal absorption, renal reabsorption,
and mobilisation in bone (DeLuca 1979). Plasma levels
of vitamin D3 vary across the seasons, with latitude,
and with occupation (Neer 1985). Likewise, calcium
levels vary with the seasons (Neer 1985), suggesting
annual regulation of biological functions as a consequence
of changes in vitamin D3 levels. Soltriol also
exerts more direct e§ects at the cellular level by other
mechanisms including gene regulation (Hannah and
Norman 1994) and calcium binding proteins (Celio
1990).
Multiple specific target sites for soltriol exist in both
central and peripheral nervous systems (Stumpf et al.
1982; Stumpf and OíBrien 1987), suggesting that vitamin
D3 levels will impact on numerous psychological
functions via multiple mechanisms, not least of which
is altered neuronal calcium metabolism. Of particular
relevance to seasonal mood changes is the dorsal raphe
nucleus (DRN), which extensively innervates the forebrain
and limbic areas via the ascending serotonergic
system (Baumgarten 1993). 5-HT is implicated in a
wide range of behaviours and psychological states,
including mood (Meltzer 1990), food consumption
(Curzon 1990; Jimerson et al. 1990), and sleep (Adrien
1995).
Experiments involving SAD patients using phototherapy
have been di¶cult to interpret, largely due
to the potential placebo e§ects of the treatment
(Eastman 1990a). However, during winter when vitamin
D3 levels are known to be low (Neer 1985), oral
supplementation using vitamin D3 allows for control
of such e§ects. If soltriol in fact increases DRN 5-HT
levels, then increasing levels of vitamin D3 during winter
when levels are at their lowest and a§ective states
are also at their lowest should be expected to result in
enhanced mood in normal subjects.
Materials and methods
Subjects
Subjects were 44 healthy student volunteers enrolled in an undergraduate
psychology course and recruited by advertising notices in
the department. Informed consent was obtained from all participating
subjects. There were 34 females and ten males. Ages ranged
from 18 to 43 years, with a mean of 22.0 and SD 6.57. Only subjects
not already taking vitamin supplements participated. Subjects
were randomly assigned to one of three vitamin D3 supplementation
levels in a between-subjects design: 0 IU/day; 400 IU/day;
800 IU/ day. The majority of subjects received course credit for participation.
Materials
Vitamin D3 capsules were not commercially available in pure form,
but were only available in combination with other vitamins and
minerals. Vitamin D3 (400 IU) in combination with vitamin A
(4000 IU) ìNatural Nutritionî and vitamin A (5000 IU) ìNatures
Ownî were obtained from a local health food store. The vitamin
A was used as a placebo control.
The Positive and Negative A§ect Schedule (PANAS) (Watson
et al. 1988) was used as a self report measure of both positive and
negative a§ectivity. The scale contains measures of Positive A§ect
(PA) and Negative A§ect (NA), which are considered by Watson
et al. (1988) to be unrelated. The scales correlate well with the
Nowlis Mood Adjective Checklist (Kennedy-Moore et al. 1992).
The PANAS uses a 5-point Likert type scale with ten adjectives for
PA (e.g. enthusiastic, interested, determined) and ten adjectives for
NA (e.g. scared, afraid, upset). Scores on both the PA and NA
scales range from 10 to 50. The scale was preceded by the following
instructions : ìPlease rate how much each of the following words
is characteristic of the way you feel todayî.
Procedure
Each subject was issued with ten vitamin capsules to be taken two
per day, one morning and one evening, for the 5 days prior
to testing. Batches either contained ten vitamin A (vitamin
A = 10 000 IU/day) with no vitamin D3, five vitamin A and five
vitamin A and D (vitamin A = 9000 IU/day, vitamin D3 =
400 IU/day), or 10 vitamin A and D (vitamin A = 8000 IU/day,
vitamin D3 = 800 IU/day). It was assumed that the minor discrepancy
in vitamin A levels would have no e§ect. Furthermore, levels
were in the reverse direction to the hypothesised e§ect on mood.
Subjects were instructed to take one of each type of capsule per day
if their batch contained both types of capsules. The dispensation
procedure was random and double-blind. Supplementation and testing
were carried out in late winter when natural levels of vitamin
D3 were likely to be minimal. On test day, subjects were asked if
they had taken the vitamins as instructed. All subjects reported they
had followed the instructions. All subjects completed the PANAS
preceded by the following verbal instructions: ìPlease complete this
short questionnaire relating to how you feel TODAY (emphasis).
Circle the number you think most corresponds to the way you feel.
Respond reasonably quickly and donít think about your answers
too much. Your first response is usually the bestî.
Results
Cronbachís Alphas (Cronbach 1951) for the two scales
were 0.87 for PA and 0.74 for NA.
Mean PA and NA scores for the three groups are
shown in Fig. 1. Both dose groups appeared to show
enhanced PA above the controls. A one-way ANOVA
for PA between the three groups revealed a highly
significant di§erence between the three groups for PA,
[F(2,41) = 9.32, P < 0.001]. A post-hoc test using the
Student-Newman-Keuls procedure indicated that there
was no di§erence between dose levels, but both doses
exhibited enhanced PA relative to controls. A ceiling
e§ect appears to have occurred, with the high dose not
producing a stronger e§ect than the low dose. Both
dose groups appeared to exhibit lower NA with respect
to controls. However, a one-way ANOVA for NA was
not significant, [F(2,41) = 0.39, P > 0.05]. Despite not
reaching significance, the trend for NA was the opposite
of PA. The failure to reach significance may have
been due to a floor e§ect on the NA scale. The scale
320
ranges from 10 to 50 with a population norm of 16.3
(Watson et al. 1988). The control group scored even
lower than the norm, and the highly skewed distribution
towards the lower end of this scale may have meant
that any further deviation towards the lower end was
likely to be minimal. Due to the small number of males
in the sample, sex di§erences were not evaluated.
Of interest are comments made by many subjects.
Most subjects receiving the vitamin D3 supplementation
reported feeling ìreally goodî for the 5 days,
whereas none of the controls made such comments.
Discussion
Dietary supplementation of either 400 IU or 800 IU of
vitamin D3 for 5 days during late winter significantly
enhanced PA and showed evidence of reducing NA
relative to controls as measured by self-report on the
PANAS.
PA for both dose groups was raised almost a full
standard deviation above the population norm, as
reported by Watson et al. (1988). The control group
remained almost identical to the population norm. The
ceiling e§ect that appears to have occurred may have
been due to saturation of the vitamin D receptors, with
400 IU su¶cient to raise levels to maximum in healthy
subjects. This would be consistent with Holick (1994),
who found in submariners that the daily requirement
for vitamin D3 from all sources was 600 IU.
PA is claimed to be related to social activity and satisfaction,
and to the frequency of pleasant events (Clark
and Watson 1988; Watson 1988). The PA scale includes
adjectives such as enthusiastic, inspired, alert, active,
and attentive. Such adjectives would imply that subjects
receiving vitamin D3 showed evidence of higher
levels of arousal and being more alert. The mechanism
by which this occurs can only be speculated upon.
However, since 5-HT is implicated in levels of arousal
across the sleep wake cycle (Trulson and Jacobs 1979),
and deficits in this neurotransmitter are implicated in
depression (Meltzer 1990), then increased synthesis and
release of 5-HT from the DRN is a likely and plausible
explanation for this e§ect. However, such an
hypothesis does not rule out the possibility of other
neurotransmitters such as acetylcholine or even
dopamine and glutamate contributing to these e§ects.
NA was not significantly reduced below the control
group for either dose group; however, the trend was the
reverse of that for PA. The NA scale has a highly skewed
distribution, scores potentially range from 10 to 50 with
a population norm reported by Watson et al. (1988) of
16.3. The control group scored almost a half standard
deviation below this score, with both dose groups scoring
even lower again. It is most likely that this floor
e§ect with the healthy subjects was responsible for a
non-significant result. NA is claimed to be related to
self-reported stress and poor coping (Kanner et al.
1981; Wills 1986), health complaints (Tessler and
Mechanic 1978), and frequency of unpleasant events
(Stone 1981; Warr et al. 1983). The NA scale includes
adjectives such as upset, jittery, nervous, and irritable.
Once again, a reasonable and plausible explanation
would be altered levels of 5-HT. Such adjectives are
suggestive of anxiety-like symptoms, and low 5-HT has
been implicated in anxiety disorders (Charney et al.
1990; Taylor 1990).
That vitamin D3 has been demonstrated to have a
powerful e§ect on mood and varies significantly across
the seasons implies a link between the hormone and
seasonal variations in mood. Current models of the
aetiology of seasonality make reference to desynchronisation
of the circadian rhythm, thought to be regulated
through light to the eyes. The suprachiasmic
nuclei (SCN) of the anterior hypothalamus generate
electrophysiological and metabolic cycles that repeat
321
Fig. 1A, B E§ects of supplementation with vitamin D3 for 5 days
on self-reported positive a§ect (A) and negative a§ect (B).
Represented are means ± SEM on the Positive and Negative A§ect
Scale (Watson et al. 1988) for control, 400 IU/day (low dose), and
800 IU/day (high dose)
about every 24 h (Inouye and Kawamura 1979), with
the rhythm synchronised to the photoperiod.
Elimination of photic input to the brain results in a
free-running rhythm and destruction of the SCN causes
loss of circadian rhythmicity (Rusak 1977; Morin and
Cummings 1981).
The pineal receives signals from the eyes by way of
the SCN and paraventricular nucleus of the hypothalamus
(McKinley and Oldfield 1990). This results in a
daily rhythm of melatonin production in the pineal with
darkness being stimulatory and light being inhibitory.
Further input to the pineal is received from the superior
colliculi, dorsal lateral geniculate nuclei, and lateral
and medial habenular nuclei (McKinley and
Oldfield 1990). All input nuclei to the pineal are
immunoreactive to the vitamin D3 dependent calcium
binding protein, calbindin-D28k (Celio 1990). From
this, it could be concluded that vitamin D3 will a§ect
melatonin synthesis directly and hence modulate circadian
rhythms. The desynchronisation seen in SAD is
thus potentially a secondary e§ect of low levels of vitamin
D3.
Further evidence also suggests that vitamin D3 will
a§ect circadian rhythms indirectly. 5-HT has been
implicated as a regulator of rhythms (Morin et al.
1990). 5-HT regulates release of adrenocorticotropin
hormone, growth hormone, prolactin, luteinising hormone,
and follicle stimulating hormone from the anterior
pituitary (Ettigi 1983). Thyroid hormones, sex
steroids, and glucocorticoids have also been shown to
modify circadian rhythms (McEachron and Schull
1993). All of these hormones are a§ected directly or
indirectly by vitamin D3.
The full clinical syndrome of SAD is represented by
an array of symptoms other than depression. The full
range of symptoms include irritability, anxiety,
increased appetite, carbohydrate craving, increased
weight, increased duration and poorer quality sleep,
daytime drowsiness, decreased libido, work and interpersonal
di¶culties, and menstrual irregularities
(Rosenthal et al. 1985; Rosenthal and Wehr 1987). No
explanation appears to have been put forward to
account for these associated symptoms of SAD as a
consequence of changes to circadian rhythms by light
through the eyes. However, the evidence would support
the notion that these symptoms are a consequence of
vitamin D3 deficiency via either direct or indirect e§ects.
Low levels of 5-HT have a role in anxiety (Charney
et al. 1990; Taylor 1990), sleep-wakefulness (Wauquier
and Dugovic 1990), appetite and eating disorders
(Curzon 1990; Jimerson et al. 1990) and even obsessions,
compulsions, and aggressive impulses (Insel
et al. 1990). Vitamin D3 has more direct e§ects :
improved glucose induced release of insulin (Chertow
et al. 1980) may result in increased energy levels, control
of appetite and increased 5-HT due to increased
availability of its precursor tryptophan (Fernstrom and
Wurtman 1971); increased synthesis of acetylcholine
(Sonnenberg et al. 1986) and immune modulation
(Manalagos et al. 1991) may result in altered sleep; and
increases in LH and testosterone (Sonnenberg et al.
1986) may enhance libido. Light therapy has been
shown to be e§ective in the treatment of late luteal
phase dysphoric disorder (Parry et al. 1993), as has the
5-HT agonist fluoxetine (Steiner et al. 1995). These
e§ects are most likely brought about by increased 5-
HT and LH re-establishing more stable menstrual hormone
rhythms.
Vitamin D3 deficiency provides a compelling and
parsimonious explanation for seasonal variations in
mood. Alterations to circadian rhythms are most likely
a consequence of the changes in vitamin D3 status, and
the therapeutic e§ects of light treatment may to some
extent be mediated in this way. In contemporary western
society, people generally obtain little exposure to
sunlight (Wurtman and Wurtman 1989; Eastman
1990b), suggesting consequences for low levels of vitamin
D3. Further investigations are needed into how
vitamin D3 a§ects circadian rhythms, seasonal rhythms,
and menstrual rhythms. Direct investigations with SAD
su§erers, di§erences between males and females as to
the e§ects of vitamin D3 on mood and other behaviours
(e.g. food consumption, sleep), supplementation
at di§erent stages of the menstrual cycle, and doseresponse
relationships all require attention.
Acknowledgements This work was submitted to the Department
of Psychology, The University of Newcastle, in part fulfilment of
the requirements for the degree of Bachelor of Science with Honours.
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