1. The Beginning of Light Therapy
Daniel F. Kripke, M.D.
University of California, San Diego
This slide set was presented at the Society for Light Treatment and Biological Rhythms, June 15, 2015, meeting at the University of California, San Diego.
Anotations, some minor revisions, and slides of two recent studies were added in December, 2016
From presentation at the Society for Light Treatment and Biological Rhythms, San Diego, CA, USA, June 27, 2015

2. Genesis, Chapter 1
3 And God said, Let there be light: and there was light.
4 And God saw the light, that it was good: and God divided the light from the darkness.
That light is good is a very old idea. Here is a quotation from the beginning of the Bible. Other ancient sources had the same idea.

3. Old & Ancient History Seasonality: Hippocrates, Aristotle, etc.
Hippocratic & Aesclapian temples
Pinel & Esquirol
Spas and “a little fresh air”
Kellogg: arc lights and buttermilk
Finsen
Wehr & Rosenthal. Am J Psychiatry 1989; 146:
Hippocrates and Aristotle wrote about the seasonality of mood.
The Hippocratic and Aesclapian temples in Greece appeared to keep worshippers seeking cure in daylight for long intervals.
Wehr and Rosenthal, Am J Psychiatry 1981, 146: describe writings of Pinel and Esquirol about using light for treatment.
The idea of seeking cures at spas and by getting “fresh air” was certainly prevalent by the 19th Century.
J. H. Kellogg. Light Therapeutics, Battle Creek, MI, 1910
Free Google book

4. J. H. Kellogg published Light Therapeutics in Battle Creek, Michigan in Kellogg was treating thousands of patients with special lighting. This interesting book is available free from Google Books. Other somewhat similar books appeared at about the same time. Also see the following slides.
J. H. Kellogg. Light Therapeutics, Battle Creek, MI, Free Google book

5. From Kellogg

6. From Kellogg

7. ARC LIGHTS and BUTTERMILK
From Kellogg, 1910

8. Niels Finsen Nobel Prize, 1903 Sunlight for cutaneous tuberculosis.
Niels Finsen received a Nobel prize in 1903 for sunlight treatment of cutaneous tuberculosis.

9. PHOTOPERIOD EFFECTS Hoffman RA, Reiter RJ.
Responses of some endocrine organs of female
hamsters to pinealectomy and light.
Life Sci 1966;5:
Hoffman and Reiter were leaders in describing photoperiod and pinealectomy effects on hamster endocrine responses.
In the early 1970’s, Dr. Hoffman was kind enough to pay Dr. Kripke a visit and alert him to the possible relevance of this research to the topic of circadian rhythms and mood disorders.

10. Elliott JA, Stetson MH, Menaker M. Science 1972; 178:771-3.
Elliott’s work with Stetson and Menaker was perhaps the first to demonstrate that photoperiodic seasonal measurement worked through circadian clocks mechanisms
Elliott JA, Stetson MH, Menaker M.
Science 1972; 178:771-3.
Regulation of testis function in golden hamsters:
a circadian clock measures photoperiodic time.

11. Affective disturbances could be evolutionary
remnants of the photoperiodic seasonal responses in animals
internal desynchronization uncoupling free-running component internal phase-angle relationships genetic and age-related features
A number of the hypotheses about photoperiodism reiterated below were heralded in the 1978 article of Kripke et al.

12. Lewy AJ, Wehr TA, Goodwin FK, Newsome DA, Markey SP.
500 lux
Dark asleep
1500 lux
2500 lux
The landmark paper of Lewy et al. showed that human melatonin was suppressed by very bright light at night, requiring at least 2500 lux for extreme suppression. Subsequent studies have shown that in other conditions, light much less bright can suppress human melatonin.
Lewy AJ, Wehr TA, Goodwin FK, Newsome DA, Markey SP.
Light suppresses melatonin secretion in humans.
Science ;210:

13. Dr. Kripke’s short presentation at a Biological Psychiatry meeting in Stockholm in 1981, published that same year, may have been the first placebo-controlled clinical trial of bright light treatment for depression. Only one hour of bright light (about 10,000 lux) had an effect given from 2 to 1 hours before the usual time of awakening. The small advantage 1 hour of bright light (about 15% on Hamilton Depression Ratings as compared with placebo red light) was considered disappointingly small at the time, but we now realize it was similar to the benefits of fluoxetine and similar antidepressants over 8 weeks.

14. CASE REPORT of WINTER DEPRESSION
Although a few cases of winter depression had been described previously, Lewy’s single case report of the bright light treatment of Herbert Kern was a stimulus for a focus on bright light treatment of SAD (winter depression).

15. Psychopharm Bull 1983;19:526-530. Added subjects
Kripke et al. published another small placebo-controlled trial of 1-hour bright light in non-seasonal depressives, searching for the optimal timing.
Psychopharm Bull
1983;19:

16. Arch Gen Psychiat
1984;41:72-80.
Rosenthal et al. reported dramatic benefits in a small placebo-controlled trial of 1-week bright light for Seasonal Affective Disorder (SAD). However, subsequent studies that better-equalized expectations for bright light and placebo did not generally confirm the size of this benefit, though meta-analyses show that the light treatment benefit is reliably significant.

17.
Founded in 1988, the Society for Light Treatment and Biological Rhythms has brought together the growing international group of light treatment scientists. It remains a premier source for information about bright light research. The SLTBR.org web site is highly informative.

18. Neumeister et al. showed in a placebo-controlled study that the dramatic one-day benefit of sleep deprivation could be prolonged by adding bright light treatment, so that relapse was lessened. This study has led to further development of combined double and triple therapies (light plus sleep restriction plus sleep-time advances).

19. In 1998, Kripke reviewed small groups of controlled trials to suggest that light treatment might be more powerful (and certainly faster-acting) than antidepressants. Moreover, for treatment of non-seasonal depressions, there was an early suggestion that combinations with antidepressants (bottom 3 studies) produced even better results than bright light alone.
Kripke, JAD, 1998;49:

20. Taking the slowest-acting and fastest-acting drug and light treatments from this small compendium (previous slide), it was apparent that the net benefits of light treatment appeared much faster though not necessarily greater than longer treatment with antidepressants. At this time, controlled trials of bright light of 8 weeks and more were not available.

21. In an excellent controlled comparative trial, Lam et al
In an excellent controlled comparative trial, Lam et al. showed that fluoxetine and bright light had supprisingly similar benefits at 8 weeks, but the bright light was more effective after the first week. This study had no placebo group to show what part of these benefits might have been placebo-based or spontaneous remission.
Am J Psychiatry 2006;163:
© American Psychiatric Association. All rights reserved.

22. Copyright © 2016 American Medical Association. All rights reserved.
From: Lam, et al. Efficacy of Bright Light Treatment, Fluoxetine, and the Combination in Patients With Nonseasonal Major Depressive Disorder: A Randomized Clinical Trial
JAMA Psychiatry. 2016;73(1): doi: /jamapsychiatry
Lam et al. (2016) examined bright light treatment effects in nonseasonal major depressive disorders. The improved design was a 2X2 randomized placebo-controlled trial of bright light vs dummy negative ionizer and of fluoxetine vs placebo. After 8 weeks, bright light was significantly better than placebo, as was the treatment combination. Although the statistical analysis was presented without claiming an advantage, it appeared that bright light was more than 3 times as effective as fluoxetine. Further, the combination treatment appeared synergistic. That is, the effects of combination treatment were greater than the sum of the two treatment effects.
cP < .05 vs placebo.
Date of download: 12/4/2016
Copyright © 2016 American Medical Association. All rights reserved.

23. ---SLEEPY--- MELATONIN TEMPERATURE Preferred Sleep
In the following group of slides, a neurobiologic theory of depression mechanisms is presented, leading from circadian delayed sleep phase to photoperiodic endocrine responses in the hypothalamus.
In a model normal adult shown here, melatonin begins to rise 1-2 hours BEFORE sleep onset and begins to fall just about the time of awakening. Core body temperature has it’s low point about 2 hours before waking.
---SLEEPY---
NOON PM MN AM NOON
Preferred Sleep

24. ---SLEEPY--- DELAYED SLEEP PHASE: MELATONIN TEMPERATURE
In the person with delayed sleep phase syndrome, the interval of sleepiness starts and ends substantially after the beginning and end of the preferred sleep time. Temperature and melatonin circadian rhythms, etc., are correspondingly late. Accordingly, patients with a delayed sleep phase “syndrome” or “disorder” experience trouble falling asleep at bedtime and trouble awakening and arising in the morning.
---SLEEPY---
NOON PM MN AM NOON
Preferred Sleep

25. DEPRESSION EVENING PERSON MORNING PERSON MELATONIN MIDNIGHT
A related phenomenon to delayed (or advanced) sleep phases is the morningness-eveningness dimension, referring mainly to feelings and energy at particular times out of bed. Morning people are energetic early in the day and evening people are energetic towards the end of their wake period. Depressed patients tend to display more than average eveningness tendency.
Morning people have early melatonin curves in clock time. Evening people have later melatonin curves. However, what is “normal” depends on social factors, work schedules, etc.
MIDNIGHT

26. MELATONIN DURATION ONSET OFFSET SLEEP
Melatonin typically rises an hour or two before sleep onset, and pineal scretion begins to fall rapidly just about the time of awakening (though melatonin is found in the blood for an hour or two after arising). Exposure to bright light upon awakening is typically a factor. The melatonin duration and the duration of the sleep period have been found to be somewhat correlated
ONSET
OFFSET

27. MELATONIN DURATION ONSET OFFSET SLEEP
Bright light in the morning, soon after arising, suppresses the end of the melatonin elevation, and eventually, pushes the melatonin elevation earlier, along with the entire circadian system and sleep tendency.
ONSET
OFFSET

28. MELATONIN DURATION SLEEP ONSET OFFSET 7am 10am
After morning bright light treatment, evening melatonin onset and evening sleep onset will advance in a person having had a delayed sleep phase. These phenomena are typically observed among patients with winter depressions treated with morning bright light. Probably, similar changes occur among those with nonseasonal unipolar or bipolar depressions when treated with bright light.
7am am
ONSET
OFFSET

29. MELATONIN DURATION ONSET OFFSET Morning propranolol for SAD: SLEEP
Schlager DS.
Am J Psychiatry.
1994;151(9):
MELATONIN
SLEEP
Morning propranolol also suppresses morning melatonin and benefits SAD. This seminal idea needs much more study.
ONSET
OFFSET

30. MELATONIN Dardente et al. Curr Biol 2010;20:2193-2198
Masumoto et al. Curr Biol 2010;20:
Dardente et al. and Masumoto et al. both showed in 2010 that in animals, melatonin suppresses hypothalamic pars tuberalis EYA3 gene expression when melatonin offset is delayed. The EYA3 peak expression occurs about 12 hours after dark-onset in mammalian experimental studies.
Clicking to the next slide shows the transition.
MELATONIN
Pars TuberalisEYA3
12 HOURS

31. EYA3 LONG SLEEP or WINTER 12 HOURS
As melatonin offset becomes later (due to winter expansion of the melatonin secretion duration, or long sleep, or delayed sleep phase, the EYA3 peak expression may be suppressed.
EYA3
12 HOURS

32. EYA3 LIGHT TREATMENT 12 HOURS
Theoretically, morning light treatment of a patient with delayed melatonin offset (e.g., depressed or with long sleep or delayed sleep phase) would move melatonin offset earlier and restore EYA3 transcription.
EYA3
12 HOURS

33. DELAYED MELATONIN OFFSET
DSPS or WINTER
The role of Pars Tuberalis, EYA3, T3, and melatonin in photoperiodic responses has been well-demonstrated, first in quail and then in mammals, but as yet there is little human study because of the obvious experimental difficulties.
EYA3
12 HOURS

34. A review of the neurobiology of photoperiodic hypotheses of
depression and mania was presented in 2015, emphasizing work left to be done.
A more detailed review of the literature concerning the theory relating hypothalamic photoperiodic responses to depression is presented in this review paper. An elaboration of the theory suggests that in mania, suprachiasmatic nucleus circadian rhythms may become bifurcated, perhaps leading to bifurcation of the melatonin secretion from the pineal.

35. A dramatic phase-shift theory of bipolar disorder was presented in 2016, but it did not support the photoperiodic theories.
Moon, J. H., Cho, C. H., Son, G. H., Geum, D., Chung, S., Kim, H., Kang, S. G., Park, Y. M., Yoon, H. K., Kim, L., Jee, H. J., An, H., Kripke, D. F., and Lee, H. J. Advanced Circadian Phase in Mania and Delayed Circadian Phase in Mixed Mania and Depression Returned to Normal after Treatment of Bipolar Disorder. EBioMedicine
This Moon et al. paper provides some of the best longitudinal data about circadian phase shifts in recovery from bipolar mania and depression. The data show that circadian rhythms of bipolar-depressed patients were delayed at the time of acute hospitalization (blue), later advancing to normal by the time of hospital discharge. This evidence of phase delay remitting to normal phase was consistent with the photoperiodic hypotheses of depression just presented. The patients who displayed mania at the time of admission had rhythms at least 180 degrees advanced: during remission, some the rhythms of some of the manics delayed to normal and others reached normal phases by advance transitions. No bifurcation of single biologic measures was observed in these manics, but there was an apparent desynchronization of some circadian rhythm phases (e.g., cortisol) with sleep/wake and activity that remained in normal phase throughout. It would be conceivable that this apparent phase desynchronization resulted from bifurcation of the circadian phases of various suprachiasmatic nucleus cell groups.
Figure Legend:
The shifting of acrophases of circadian rhythms in bipolar disorder patients. Note that the acrophase is the timing of the peak of the best-fitting sine curve. (a) The acrophase transitions of salivary cortisol circadian rhythms in bipolar patients compared to controls as the circadian peaks shifted in timing. (b) The acrophase transitions of the relative PER1/ARNTL expression circadian rhythms in bipolar patients compared to controls. The outer circular axis indicates the clock time of each acrophase assessment for each patient. Acrophases of circadian rhythms of bipolar patients were observed over the course of hospitalization. Evaluation was performed at acute states (near start of hospitalization), and every two weeks into recovery states (at the end of hospitalization). The arrow presents the direction of change in acrophase of the circadian rhythm from the acute state to the recovery state of each patient. If the duration of hospitalization was no longer than 2weeks, there were only initial and final assessments, so the acrophase arc is an arrow that has a solid circle at the time of the first acute acrophase assessment and the head of the arrow pointing to the recovery acrophase. If the duration of hospitalization was longer than 2weeks, there were sometimes intermediate and final assessments, with acrophases illustrated as two or three arrow heads along the arc. Red and orange arrows indicate the shifting of acrophase of circadian rhythms in manic episodes, green arrows indicate that of mixed episodes, and blue arrows indicate that of depressive episodes. The gray sector indicates the range of acrophases for the healthy controls. The radius of each arc was arbitrarily chosen to contrast the different groups of participants, and does not represent the amplitudes of the circadian rhythms.
EBioMedicine  , DOI: ( /j.ebiom )
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