SALT LIKE CITY— Treatment for patients with circadian rhythm disorders is being cast in a new light—blue. Researchers believe that blue light therapy, though still in the experimental stage, could help patients with certain types of sleep and mood disorders, improve alertness during shift work, overcome jet lag, and even help resolve circadian disruptions in astronauts during spaceflight.

Traditional treatment of patients with circadian rhythm disorders has been based on the premise that the suprachiasmatic nucleus, or the body’s internal clock, will only respond to bright light at a certain time of day. The fact that lower-intensity, short-wavelength blue light has been shown to be more effective than the most visible kinds of light in that regard is evidence that a separate photoreceptor system exists within the human eye, other than what is used for sight. Ultimately, color, intensity, and timing of light are all critical factors for stimulating the body clock, which regulates sleep patterns and other physiologic and behavioral functions.

"The circadian system is ubiquitous," said Leon Lack, PhD, at the 20th Anniversary Meeting of the Associated Professional Sleep Societies (APSS). "Virtually every physiologic, biochemical, and hormonal measure you can take for 24 hours shows a circadian rhythm. Most of these circadian rhythms are endogenous, and they are timed by the internal body clock." Dr. Lack is a Professor of Psychology at Flinders University of South Australia in Adelaide.

According to Dr. Lack, a normal sleep phase involves a bedtime of about 11:00 pm and wake-up time of about 7:00 am, with a core temperature minimum in the latter half of the normal sleep period. However, for people with an advanced sleep phase, the core temperature minimum might be as early as midnight. Likewise, people with a delayed circadian rhythm have a core temperature minimum as late as 7:00 or 8:00 am.

"Bright light presented just after [core temperature minimum] will cause phase advances, and bright light just before that time will cause phase delays," said Dr. Lack. "Low-intensity light will cause a small phase delay presented just before that temperature minimum. Moderate intensity light and high intensity light will cause a greater phase delay. Likewise, light presented after that point, of low, moderate, or high intensity will cause varying degrees of phase advance."

LOOKING THROUGH BLUE-COLORED GLASSES

Light boxes have been the most common tool used in light therapy, but they are large and bulky, not easily transported, and are relatively costly. So Dr. Lack and colleagues devised hi-tech glasses that deliver the same amount of light into the eyes but reduce the overall amount of light produced. "So we actually have a source that is very close to the eyes, emitting very much less light but still getting exactly the same amount of light to the retina."

Dr. Lack’s group used light-emitting diodes (LEDs), which are very efficient in converting electricity into light and have relatively narrow spectrum outputs, to compare a standard light box with two portable light sources in suppressing and phase shifting melatonin. They found that the portable LED source was an effective way of administering light to phase-shift the melatonin rhythm, with the blue-green LED light outperforming white LED light.

The investigators also carried out a phase advance study in which amber and red light, which are both long-wavelength light, were compared with short-wavelengths blue, blue-green, and green light emitted via the glasses, as well as with a no-light condition. Dim light melatonin onset (DLMO) was measured on the first evening and again on the third evening, and the glasses were worn between 6:00 and 8:00 am on two consecutive mornings. Dr. Lack’s group found that the no-light control condition was associated with no significant change. "That’s sort of interesting in a sense, that they woke up earlier than normal for two mornings in a row under dim illumination levels, and that in itself wasn’t able to produce any significant phase advance," he said. "The green, blue-green, and blue all produced significant changes from the control condition and from the amber and red conditions. The blue also had a significantly greater phase advance than the green in this experiment."

INTO THE BLUE

George Brainard, PhD, has focused much of his research on the circadian and neuroendocrine capacities of light and the use of light treatment for winter depression. In a recent study that explored short-wavelength sensitivity for the effects of light on alertness and performance, he teamed with lead investigator Steven Lockley, PhD, of the Brigham and Women’s Hospital in Boston. The researchers compared the effects of equal photon density exposure to 460-nm blue or 555-nm white light for 6.5 hours during the night. The researchers measured melatonin onset before the light exposure and then again afterward and found that subjects exposed to blue light had significantly lower subjective sleepiness ratings, decreased auditory reaction time, and fewer attention failures, compared with those exposed to white light.

"What is really astonishing about these data is that it takes 5 lux [of blue light] with this very precisely measured method of delivery of light to produce a phase delay equivalent to 10,000 lux of white light without pupil dilation and, of course, without this rigorous control," said Dr. Brainard. He is a Professor of Neurology at Thomas Jefferson University in Philadelphia.

"We’ve got a very interesting picture now," he commented. "We’ve got the development and discovery of a new sensory system, the work of many laboratories. Of course, the classic visual photoreceptor system mediates vision, and then this newly discovered system mediates biologic and behavioral effects, some of them very fast-acting and acute, some of them longer term."

BLUE FOR SAD

Dr. Brainard and colleagues also studied a cohort with seasonal affective disorder (SAD). According to Dr. Brainard, the current standard of therapy for SAD is 10,000 lux white light therapy in the morning. "As with any clinical intervention, you start with something that works, and then ultimately you try to refine it down and optimize it to its most potent elements, because then you can make it more convenient with fewer side effects."

The researchers sought to determine if blue light would be more potent than the longer-wavelength part of the spectrum. Arrays of blue LEDs were developed specifically for the study. "They are not commercially available," Dr. Brainard noted. "They are a bigger bank of light and very much in the developmental stage."

Nineteen females and five males participated in the study. All had major depression with a seasonal pattern, a score of 20 or greater on the Structured Interview Guide for the Hamilton Depression Rating Scale–SAD (SIGH-SAD), and normal sleeping patterns. They were randomly assigned, in a double-blind fashion, to receive either blue light or red light therapy daily for 45 minutes upon awakening, between 6:00 and 8:00 am, for three weeks. Each light unit measured 20 x 24 centimeters and had 267 LEDs in the array and had been given an independent hazard analysis. After one week of therapy, both groups had a reduction in symptoms, "but there was a more dramatic reduction in the blue light group," noted Dr. Brainard. "That reduction continued to go down across the three weeks in the blue light group. Compared to the red light, blue light produced a significantly stronger therapeutic response."

Dr. Brainard’s group also looked at remission rates in the cohort. "When we look at it in terms of remission, the blue light group had a 55% remission rate, and the red light group had a 31% remission rate, and that was statistically significant as well."

When comparing actual photometric and radiometric parameters, the researchers found that the blue light at less than 400 lux evoked a similar therapeutic response to that observed with the 10,000 lux of white light. The blue light also had a lower photon density and a lower microwatt level. "So much less of everything," pointed out Dr. Brainard, "whether you are counting energy, photons, or illuminance, this device achieved equivalent types of therapy in this phase I trial compared to standard therapy.

"We think that these data are supportive of the idea that blue light might have high efficacy for treating winter depression, but there are limitations to this study, and I want to be very clear about these limitations," Dr. Brainard continued. "It’s a phase I trial; it’s proof of concept. To confirm a specific wavelength effect, the trial must be done in equal photon densities, and that’s not been done yet. The study also did not do a direct comparison to 10,000 lux of white light. That’s a historical comparison. Still, we think the data are very provocative."

THE (BLUE) SKY IS THE LIMIT

It is clear that circadian rhythms, in terms of DLMO measurements in people with delayed sleep-phase syndrome, can be retimed with morning blue light, Dr. Lack commented. "Changes in circadian rhythms alone, however, do not result in a change in sleep-wake habits," he said. "We’re dealing with real people, with real contingencies and needs and habits. So it is clear to us that we need to follow the blue light treatment with instructions of about what to do to try and maintain their wake-up time in the posttreatment period. So cognitive behavior therapy or at least further instructions obviously will be necessary."

"Basically, I think the bottom line is this," Dr. Brainard continued. "A brand new sensory system has been discovered. There’s a lot of neuroanatomy and neurophysiology to be worked out on it, but it has very many exciting potential applications. Essentially, our field has an open door, an opportunity to begin exploring this in greater depth."

—Colby Stong

Suggested Reading
Glickman G, Byrne B, Pineda C, et al. Light therapy for seasonal affective disorder with blue narrow-band light-emitting diodes (LEDs). Biol Psychiatry. 2006;59:502-507.
Herljevic M, Middleton B, Thapan K, Skene DJ. Light-induced melatonin suppression: age-related reduction in response to short wavelength light. Exp Gerontol. 2005;40:237-242.
Lockley SW, Evans EE, Scheer FA, et al. Short-wavelength sensitivity for the direct effects of light on alertness, vigilance, and the waking electroencephalogram in humans. Sleep. 2006;29: 161-168.
Wright HR, Lack LC. Effect of light wavelength on suppression and phase delay of the melatonin rhythm. Chronobiol Int. 2001;18:801-808.
Wright HR, Lack LC, Partridge KJ. Light emitting diodes can be used to phase delay the melatonin rhythm. J Pineal Res. 2001;31:350-355.

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